Substituted indolealkanoic acids

ABSTRACT

Disclosed are substituted indolealkanoic acids useful in the treatment of chronic complications arising from diabetes mellitus. Also disclosed are pharmaceutical compositions containing the compounds and methods of treatment employing the compounds, as well as methods for their synthesis.

[0001] This is a continuation-in-part of application Serial No.60/080,143, filed Mar. 31, 1998.

BACKGROUND OF INVENTION

[0002] The use of aldose reductase inhibitors (ARIs) for the treatmentof diabetic complications is well known. The complications arise fromelevated levels of glucose in tissues such as the nerve, kidney, retinaand lens that enters the polyol pathway and is converted to sorbitol viaaldose reductase. Because sorbitol does not easily cross cell membranes,it accumulates inside certain cells resulting in changes in osmoticpressure, alterations in the redox state of pyridine nucleotides (i.e.increased NADH/NAD⁺ ratio) and depleted intracellular levels ofmyoinositol. These biochemical changes, which have been linked todiabetic complications, can be controlled by inhibitors of aldosereductase.

[0003] The use of aldose reductase inhibitors for the treatment ofdiabetic complications has been extensively reviewed, see: (a) Textbookof Diabetes, 2nd ed.; Pickup, J. C. and Williams, G. (Eds.); BlackwellScience, Boston, Mass. 1997.; (b) Larson, E. R.; Lipinski, C. A. andSarges, R., Medicinal Research Reviews, 1988, 8 (2), 159-198; (c)Dvornik, D. Aldose Reductase Inhibition. Porte, D. (ed), BiomedicalInformation Corp., New York, N.Y. Mc Graw Hill 1987; (d) Petrash, J. M.,Tarle, I., Wilson, D. K. Quiocho. F. A. Perspectives in Diabetes, AldoseReductase Catalysis and Crystalography: Insights From Recent Advances inEnzyme Structure and Function, Diabetes, 1994, 43, 955; (e) Aotsuka, T.;Abe, N.; Fukushima, K.; Ashizawa, N.and Yoshida, M., Bioorg. & Med.Chem. Letters, 1997, 7, 1677, (f), T., Nagaki, Y.; Ishii, A.; Konishi,Y.; Yago, H; Seishi, S.; Okukado, N.; Okamoto, K., J. Med. Chem., 1997,40, 684; (g) Ashizawa, N.; Yoshida, M.; Sugiyama, Y.; Akaike, N.;Ohbayashi, S.; Aotsuka, T.; Abe, N.; Fukushima, K.; Matsuura, A, Jpn. J.Pharmacol. 1997, 73, 133; (h) Kador, P. F.; Sharpless, N. E., MolecularPharmacology, 1983, 24, 521; (I) Kador, P. F.; Kinoshita, J. H.;Sharpless, N. E., J. Med. Chem. 1985, 28 (7), 841; (j) Hotta, N.,Biomed. & Pharmacother. 1995, 5, 232; (k) Mylar, B.; Larson, E. R.;Beyer, T. A.; Zembrowski, W. J.; Aldinger, C. E.; Dee, F. D.; Siegel, T.W.; Singleton, D. H., J. Med. Chem. 1991, 34, 108; (1) Dvornik, D.Croatica Chemica Acta 1996, 69 (2), 613.

[0004] Previously described aldose reductase inhibitors most closelyrelated to the present invention include those sighted in: (a) U.S. Pat.No. 5,700,819: 2-Substituted benzothiazole derivatives useful in thetreatment of diabetic complications, (b) U.S. Pat. No. 4,868,301:Processes and intermediates for the preparation of oxophthalazinylacetic acids having benzothiazole or other heterocyclic side chains, (c)U.S. Pat. No. 5,330,997: 1H-indazole-3-acetic acids as aldose reductaseinhibitors, and (d) U.S. Pat. No. 5,236,945: 1H-indazole-3-acetic acidsas aldose reductase inhibitors. Although many aldose reductaseinhibitors have been extensively developed, none have demonstratedsufficient efficacy in human clinical trials without significantundesirable side effects. Thus no aldose reductase inhibitors arecurrently available as approved therapeutic agents in the United States;and consequently, there is still a significant need for new, efficaciousand safe medications for the treatment of diabetic complications.

SUMMARY OF THE INVENTION

[0005] This invention provides compounds that interact with and inhibitaldose reductase. Thus, in a broad aspect, the invention providescompounds of Formula I:

[0006] or pharmaceutically acceptable salts thereof wherein

[0007] A is a C₁-C₄ alkylene group optionally substituted with C₁-C₂alkyl or mono- or disubstituted with halogen, preferably fluoro orchloro;

[0008] Z is a bond, O, S, C(O)NH, or C₁-C₃ alkylene optionallysubstituted with C₁-C₂ alkyl;

[0009] R₁ is hydrogen, alkyl having 1-6 carbon atoms, halogen, 2-, 3-,or 4-pyridyl, or phenyl, where the phenyl or pyridyl is optionallysubstituted with up to three groups selected from halogen, hydroxy,C₁-C₆ alkoxy, C₁-C₆ alkyl, nitro, amino, or mono- ordi(C₁-C₆)alkylamino;

[0010] R₂, R₃, R₄ and R₅ are each independently hydrogen, halogen,nitro, or an alkyl group of 1-6 carbon atoms (which may be substitutedwith one or more halogens);

[0011] OR₇, SR₇, S(O)R₇, S(O)₂(R₇)₂, C(O)N(R₇)₂, or N(R₇)₂, wherein eachR₇ is independently hydrogen, an alkyl group of 1-6 carbon atoms (whichmay be substituted with one or more halogens) or benzyl, where thephenyl portion is optionally substituted with up to three groupsindependently selected from halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, amino,and mono- or di(C₁-C₆)alkylamino; phenyl or heteroaryl such as 2-, 3- or4-imidazolyl or 2-, 3- or 4-pyridyl, each of which phenyl or heteroarylis optionally substituted with up to three groups independently selectedfrom halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, amino, and mono- ordi(C₁-C₆)alkylamino;

[0012] phenoxy where the phenyl portion is optionally substituted withup to three groups independently selected from halogen, C₁-C₆ alkyl,C₁-C₆ alkoxy, amino, and mono- or di(C₁-C₆)alkylamino; or

[0013] a group of the formula.

[0014] where

[0015] J is a bond, CH₂, oxygen, or nitrogen; and

[0016] each r is independently 2 or 3;

[0017] R₆ is hydroxy or a prodrug group;

[0018] R_(a) is hydrogen, C₁-C₆ alkyl, fluoro, or trifluoromethyl; and

[0019] Ar represents aryl or heteroaryl, each of which is optionallysubstituted with up to five groups.

[0020] In another aspect, the invention provides methods for preparingsuch compounds.

[0021] The compounds of the invention inhibit aldose reductase. Sincealdose reductase is critical to the production of high levels ofsorbitol in individuals with diabetes, inhibitors of aldose reductaseare useful in preventing and/or treating various complicationsassociated with diabetes. The compounds of the invention are thereforeeffective for the treatment of diabetic complications as a result oftheir ability to inhibit aldose reductase.

[0022] Thus, in another aspect, the invention provides methods fortreating and/or preventing chronic complications associated withdiabetes mellitus, including, for example, diabetic cataracts,retinopathy, nephropathy, and neuropathy.

[0023] In still another aspect, the invention provides pharmaceuticalcompositions containing compounds of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

[0024] The numbering system for the compounds of Formula I is asfollows:

[0025] As noted above, the invention provides novel substituted indolealkanoic acids useful in treating and/or preventing complicationsassociated with or arising from elevated levels of glucose inindividuals suffering from diabetes mellitus. These compounds arerepresented by Formula I above.

[0026] In compounds of Formula I, the aryl and heteroaryl groupsrepresented by Ar include:

[0027] a phenyl group optionally substituted with up to 5 groupsindependently selected from halogen, an alkyl group of 1-6 carbon atoms(which may be substituted with one or more halogens), nitro, OR₇, SR₇,S(O)R₇, S(O)₂R₇ or N(R₇)₂ wherein R₇ is hydrogen, an alkyl group of 1-6carbon atoms (which may be substituted with one or more halogens) orbenzyl, where the phenyl portion is optionally substituted with up tothree groups independently selected from halogen, C₁-C₆ alkyl, C₁-C₆alkoxy, amino, and mono- or di(C₁-C₆)alkylamino, or the phenyl group maybe condensed with benzo where the benzo is optionally substituted withone or two of halogen, cyano, nitro, trifluoromethyl, perfluoroethyl,trifluoroacetyl, or (C₁-C₆) alkanoyl, hydroxy, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, (C₁-C₆)alkylthio, trifluoromethoxy, trifluoromethylthio,(C₁-C₆)alkylsulfinyl, (C₁-C₆) alkylsulfonyl;

[0028] a heterocyclic 5-membered ring having one nitrogen, oxygen orsulfur, two nitrogens one of which may be replaced by oxygen or sulfur,or three nitrogens one of which may be replaced by oxygen or sulfur,said heterocyclic 5-membered ring substituted by one or two fluoro,chloro, (C₁-C₆)alkyl or phenyl, or condensed with benzo, or substitutedby one of pyridyl, furyl or thienyl, said phenyl or benzo optionallysubstituted by one of iodo, cyano, nitro, perfluoroethyl,trifluoroacetyl, or (C₁-C₆)alkanoyl, one or two of fluoro, chloro,bromo, hydroxy, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio,trifluoromethoxy, trifluoromethylthio, (C₁-C₆)alkylsulfinyl,(C₁-C₆)alkylsulfonyl or trifluoromethyl, or two fluoro or twotrifluoromethyl with one hydroxy or one (C₁-C₆)alkoxy, or one or,preferably, two fluoro and one trifluoromethyl, or three fluoro, saidpyridyl, furyl or thienyl optionally substituted in the 3-position byfluoro, chloro, bromo, (C₁-C₆)alkyl or (C₁-C₆)alkoxy;

[0029] a heterocyclic 6-membered ring having one to three nitrogenatoms, or one or two nitrogen atoms and one oxygen or sulfur, saidheterocyclic 6-membered ring substituted by one or two (C₁-C₆)alkyl orphenyl, or condensed with benzo, or substituted by one of pyridyl, furylor thienyl, said phenyl or benzo optionally substituted by one of iodoor trifluoromethylthio, or one or two of fluoro, chloro, bromo,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio, (C₁-C₆)alkylsulfinyl,(C₁-C₆)alkylsulfonyl, or trifluoromethyl, and said pyridyl, furyl orthienyl optionally substituted in the 3-position by fluoro, chloro,(C₁-C₆)alkyl or (C₁-C₆)alkoxy;

[0030] said benzo-condensed heterocyclic 5-membered or 6-membered ringsoptionally substituted in the heterocyclic 5-membered or 6-membered ringby one of fluoro, chloro, bromo, methoxy, or trifluoromethyl;

[0031] oxazole or thiazole condensed with a 6-membered aromatic groupcontaining one or two nitrogen atoms, with thiophene or with furane,each optionally substituted by one of fluoro, chloro, bromo,trifluoromethyl, methylthio or methylsulfinyl;

[0032] imidazolopyridine or triazolopyridine optionally substituted byone of trifluoromethyl, trifluoromethylthio, bromo, or (C₁-C₆)alkoxy, ortwo of fluoro or chloro;

[0033] thienothiophene or thienofuran optionally substituted by one offluoro, chloro or trifluoromethyl; thienotriazole optionally substitutedby one of chloro or trifluoromethyl;

[0034] naphthothiazole; naphthoxazole; or thienoisothiazole.

[0035] More specific compounds of the invention are those of Formula Iwherein Ar is optionally substituted benzothiazolyl, benzoxazolyl,isoquinolyl, benzothiophen-yl, benzofuran-yl or benzimidazolyl, orsubstituted oxadiazolyl or indolyl. Other more specific compounds are ofFormula I those wherein R_(a) is trifluoromethyl, Z is a covalent bondor CH₂, R₆ is hydroxy, and each of R₂-R₅ are independently hydrogen,halogen, more preferably bromo or chloro, C₁-C₂ alkyl, phenoxy,benzyloxy, or C₁-C₂ alkoxy, and R₁ is hydrogen or methyl.

[0036] Preferred compounds of the invention are those wherein Z is acovalent bond, R₆ is hydroxy, Ar is optionally substitutedbenzothiazol-2-yl, benzothiazol-5-yl, benzoisothiazol-3-yl,benzoxazol-2-yl, 2-quinolyl, 2-quinoxalyl, oxazolo[4,5-b]pyridine-2-yl,benzothiophen-2-yl, benzofuran-2-yl, or thazolo[4,5-pyridine-2-y,thieno[2,3-b]pyridine2-yl, imidazo[1,5-a]pyridine-2-yl, or indol-2-yl,or substituted 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl,isothiazol-5-yl, isothiazol-4-yl, 1,3,4-oxadiazol-5-yl,1,2,5-thiadiazol-3-yl, oxazol-2-yl, thiazol-2-yl, or thiazol-4-yl, R₂-R₅are independently hydrogen, halogen, more preferably bromo or chloro,C₁-C₂ alkyl, phenoxy, benzyloxy or phenyl where each phenyl portion isoptionally substituted with C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, hydroxy,amino or mono- or di (C₁-C₆) alkylamino R_(a) is hydrogen,fluro or C₁-C₂alkyl, and R₁ is hydrogen or methyl.

[0037] Other preferred compounds are those wherein the methylene bridgeconnecting the indolyl group with Ar is located alpha with respect to anitrogen atom in Ar, e.g. wherein Ar is benzoxazol-2-yl or1,2,4-oxadiazol-3-yl mentioned above.

[0038] Other more specific compounds of the invention are those whereinZ is a covalent bond, R₆ is hydroxy, R_(a) is hydrogen, Ar is optionally4,5,6 or 7 benzo-substituted benzothiazolyl, benzoxazolyl,benzimidazolyl, benzothiophenyl, benzofuranyl, or indolyl, or Ar is2-benzothiazolyl substituted on benzo by one trifluoroacetyl ortrifluoromethylthio, or one or two of fluoro chloro, bromo, hydroxy,methyl, methoxy, trifluoromethyl, trifluoromethoxy, trifluoromethylthio,or one or, preferably, two fluoro and one trifluoromethyl, or two fluoroor two trifluoromethyl with one methoxy, or three fluoro, or by6,7-benzo, and those wherein one of R₂ and R₃ is hydrogen, fluoro,chloro, bromo or methyl, and one of R₄ and R₅ is hydrogen, or chloro,bromo, methyl, isopropyl, methoxy, nitro or trifluoromethyl; or R₃ andR₄ is 5, 6-difluoro, R_(a) is hydrogen; and those wherein Ar isoptionally substituted benzothiazol-2-yl or quinoxalyl and R₃ and R₄ areeach chloro, and R₁ is hydrogen or methyl.

[0039] Further more specific compounds are those wherein Z is a covalentbond, R₆ is hydroxy, Ar is optionally substituted benzothiazol-2-yl, R₃and R₄ are hydrogen, and R₅ is methyl; those wherein Z is a covalentbond, R₆ is hydroxy, R₃, R₄ and R₅ are hydrogen, chloro, fluoro, bromoor C₁-C₂ alkyl, R_(a) is hydrogen, and Ar is optionally 4,5,6 or 7benzosubstituted benzothiazolyl-2-trifluoromethyl,benzoxazolyl-2-trifluoromethyl, benzimidazolyl-2-trifluoromethyl,benzofuran-2-trifluoromethyl, benzofuran-3-trifluoromethyl,benzothiophen-2-trifluoromethyl, benzothiophen-3-trifluoromethyl,indolyl-2-trifluoromethyl, or indolyl-3-trifluoromethyl; and thosewherein Z is CH₂, R₆ is hydroxy, Ar is optionally substitutedbenzothiazol-2-yl, benzothiazol-5-yl, benzoisothiazol-3-yl,benzoxazol-2-yl, 2-quinolyl, 2-quinoxalyl, oxazolo[4,5-b]pyridine-2-yl,or thiazolo[4,5-b]pyridine-2-yl, or substituted 1,2,4-oxadiazol3-yl,1,2,4-oxadiazol-5-yl, isothiazol-5-yl, isothiazol4-yl,1,3,4-oxadiazol-5-yl, 1,2,5-thiadiazol-3-yl, oxazol-2-yl, thiazol-2-yl,or thiazol-4-yl, and R₃, R₄ and R₅ are independently hydrogen, chloro,fluoro, bromo, C₁-C₂alkyl, or trifluoromethyl, and R_(a) is hydrogen.

[0040] Generally, R₁ in the specific compounds described above ishydrogen, halogen, preferably chloro or fluoro, C₁-C₆ alkyl, or phenyloptionally substituted with with up to three groups independentlyselected from halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, amino, and mono- ordi(C₁-C₆)alkylamino. Preferred R₁ groups are hydrogen and methyl.

[0041] Preferred compounds of the invention include those where Ar inFormula I is substituted phenyl, i.e., compounds of Formula II:

[0042] wherein

[0043] A is a C₁-C₄ alkylene group optionally substituted with C₁-C₂alkyl;

[0044] Z is a bond, or C₁-C₃ alkylene optionally substituted with C₁-C₂alkyl;

[0045] R_(a) is hydrogen, C₁-C₆ alkyl, chloro, bromo, fluoro, ortrifluoromethyl;

[0046] R₁ is hydrogen, C₁-C₆ alkyl, fluoro, or phenyl optionallysubstituted with up to three groups independently selected from halogen,C₁-C₆ alkyl, C₁-C₆ alkoxy, amino, and mono- or di (C₁-C₆)alkylamino;

[0047] R₂, R₃, R₄ and R₅ are each independently hydrogen, halogen, analkyl group of 1-6 carbon atoms (which may be substituted with one ormore halogens), nitro, OR₇, SR₇, S(O)R₇, S(O)₂N(R₇)₂, C(O)N(R₇)₂, orN(R₇)₂, wherein each R₇ is independently hydrogen, an alkyl group of 1-6carbon atoms (which may be substituted with one or more halogens) orbenzyl, where the phenyl portion is optionally substituted with up tothree groups independently selected from halogen, C₁-C₆ alkyl, C₁-C₆alkoxy, amino, and mono- or di(C₁-C₆)alkylamino;

[0048] phenyl or heteroaryl such as 2-, 3- or 4-imidazolyl or 2-, 3-, or4-pyridyl, each of which phenyl or heteroaryl is optionally substitutedwith up to three groups independently selected from halogen, C₁-C₆alkyl, C₁-C₆ alkoxy, amino, and mono- or di(C₁-C₆)alkylamino;

[0049] phenoxy where the phenyl portion is optionally substituted withup to three groups independently selected from halogen, C₁-C₆ alkyl,C₁-C₆ alkoxy, amino, and mono- or di(C₁-C₆)alkylamino; or

[0050] a group of the formula

[0051] where

[0052] J is a bond, CH₂, oxygen, or nitrogen; and

[0053] each r is independently 2, or 3;

[0054] R₆ is hydrogen, an alkoxy group of 1-6 carbon atoms, or —O⁻M⁺where M⁺ is a cation forming a pharmaceutically acceptable salt; and

[0055] R₈, R₉, and R₁₀, are independently hydrogen, fluorine, chlorine,bromine, trifluoromethyl or nitro.

[0056] Other preferred compounds of the invention are those where Ar isa substituted benzothiazole, i.e., compounds of Formula III:

[0057] wherein

[0058] A is a C₁-C₄ alkylene group optionally substituted with C₁-C₂alkyl;

[0059] Z is a bond, or C₁-C₃ alkylene optionally substituted with C₁-C₂alkyl;

[0060] R_(a) is hydrogen, C₁-C₆ alkyl, chloro, bromo, fluoro, ortrifluoromethyl;

[0061] R₁ is hydrogen, C₁-C₆ alkyl, halogen, preferably chloro orfluoro, or phenyl optionally substituted with with up to three groupsindependently selected from halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, amino,and mono- or di(C₁-C₆)alkylamino;

[0062] R₂, R₃, R₄ and R₅ are each independently hydrogen, halogen, analkyl group of 1-6 carbon atoms (which may be substituted with one ormore halogens), nitro, OR₇, SR₇, S(O)R₇, S(O)₂N(R₇)₂ C(O)N(R₇)₂ orN(R₇)₂, wherein each R₇ is independently hydrogen, an alkyl group of 1-6carbon atoms (which may be substituted with one or more halogens) orbenzyl, where the phenyl portion is optionally substituted with up tothree groups independently selected from halogen, C₁-C₆ alkyl, C₁-C₆alkoxy, amino, and mono- or di(C₁-C₆)alkylamino;

[0063] phenyl or heteroaryl such as 2-, 3- or 4-imidazolyl or 2-, 3-, or4-pyridyl, each of which phenyl or heteroaryl is optionally substitutedwith up to three groups independently selected from halogen, C₁-C₆alkyl, C₁-C₆ alkoxy, amino, and mono- or di(C₁-C₆)alkylamino;

[0064] phenoxy where the phenyl portion is optionally substituted withup to three groups independently selected from halogen, C₁-C₆ alkyl,C₁-C₆ alkoxy, amino, and mono- or di(C₁-C₆)alkylamino; or

[0065] a group of the formula

[0066] where

[0067] J is a bond, CH₂, oxygen, or nitrogen; and

[0068] each r is independently 2 or 3;

[0069] R₆ is hydroxy, C₁-C₆ alkoxy, or —O⁻M⁺ where M⁺ is a cationforming a pharmaceutically acceptable salt; and

[0070] R₁₁, R₁₂, R₁₃ and R₁₄ are independently hydrogen, halogen, nitro,hydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkylthio, trifluoromethyl,trifluoromethoxy, C₁-C₆ alkylsulfinyl, or C₁-C₆ alkylsulfonyl.

[0071] In preferred compounds of Formula III, the R₂, R₃, R₄ and R₅substituents, in combination, represent one of bromo, cyano or nitro,one or two of fluoro, chloro, hydroxy, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, ortrifluoromethyl, or two fluoro or two methyl with one hydroxy or one(C₁-C₆)alkoxy, or one or, preferably, two fluoro and one methyl, orthree fluoro groups. Particularly preferred R₂, R₃, R₄ and R₅substituents are, independently, fluorine, chlorine, nitro, andtrifluoromethyl.

[0072] In preferred compounds of Formulas II and III, A is preferablymethylene, methylene substituted with a methyl group, or ethylene.

[0073] Preferred compounds according to Formula II above include thosewherein R₈ is fluorine, R₉ is hydrogen and R₁₀ is bromine or thosewherein R₈ and R₁₀ are hydrogens and R₉ is nitro.

[0074] Preferred compounds of Formula III above are thosewherein thebenzothiazole moiety is substituted with nitro, one, two, or three offluoro, one or two of chloro, or at least one trifluoromethyl group.More preferred compounds of Formula II are those where A is methylene,R₁ is hydrogen or methyl, Z is a bond, and R₆ is hydroxy or C₁-C₆alkoxy.

[0075] Still more preferred compounds of Formula II are those whereinR₁₁, R₁₂ and R₁₄ are fluorines and R₁₃ is hydrogen. Other more preferredcompounds of Formula II are those where R_(a) is methyl or hydrogen, Zis methylene or, more preferably, a bond, A is CHF or C₁ or C₂ alkylene,preferably methylene, R₁ is methyl or hydrogen, and R₁₁, R₁₂ and R₁₄ arehalogens or C₁-C₃ alkyl. Still other more preferred compounds of FormulaIII are those where R_(a) is methyl or hydrogen, Z is methylene or, morepreferably, a bond, A is CHF or C₁ or C₂ alkylene, R₁ is methyl orhydrogen, and R₁₁, R₁₂ and R₁₄ are fluorines or chlorines.

[0076] Particularly preferred compounds of Formula I are those where R₃and R₄ are independently hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, orhalogen, and R_(a) is methyl or hydrogen, Z is a bond, A is methylene,methyl substituted methylene, or ethylene, R₁ is methyl or hydrogen, andR₁₁, R₁₂ and R₁₄ are fluorines or chlorines.

[0077] The term “prodrug group” denotes a moiety that is converted invivo into the active compound of formula I wherein R₆ is hydroxy. Suchgroups are generally known in the art and include ester forming groups,to form an ester prodrug, such as benzyloxy,di(C₁-C₆)alkylaminoethyloxy, acetoxymethyl, pivaloyloxymethyl,phthalidoyl, ethoxycarbonyloxyethyl, 5-methyl-2-oxo-1,3-dioxol-4-ylmethyl, and (C₁-C₆)alkoxy optionally substituted by N-morpholino andamide-forming groups such as di(C₁-C₆)alkylamino. Preferred prodruggroups include hydroxy, C₁-C₆ alkoxy, and O⁻M⁺ where M⁺ represents acation. Preferred cations include sodium, potassium, and ammonium. Othercations include magnesium and calcium. Further preferred prodrug gropsinclude O⁼M⁺⁺ where M⁺⁺ is a divalent cation such as magnesium orcalcium.

[0078] In certain situations, compounds of Formula I may contain one ormore asymmetric carbon atoms, so that the compounds can exist indifferent stereoisomeric forms. These compounds can be, for example,racemates or optically active forms. In these situations, the singleenantiomers, i.e., optically active forms, can be obtained by asymmetricsynthesis or by resolution of the racemates. Resolution of the racematescan be accomplished, for example, by conventional methods such ascrystallization in the presence of a resolving agent, or chromatography,using, for example a chiral HPLC column.

[0079] Representative compounds of the present invention include thepharmaceutically acceptable acid addition salts of compounds where R₆includes basic nitrogen atom, i.e, an alkylamino or morpholino group. Inaddition, if the compound or prodrug of the invention is obtained as anacid addition salt, the free base can be obtained by basifying asolution of the acid salt. Conversely, if the product is a free base, anaddition salt, particularly a pharmaceutically acceptable addition salt,may be produced by dissolving the free base in a suitable organicsolvent and treating the solution with an acid, in accordance withconventional procedures for preparing acid addition salts from basecompounds.

[0080] Non-toxic pharmaceutical salts include salts of acids such ashydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic,toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric,maleic, hydroiodic, alkanoic such as acetic, HOOC—(CH₂)n-ACOOH where nis 0-4, and the like. Non-toxic pharmaceutical base addition saltsinclude salts of bases such as sodium, potassium, calcium, ammonium, andthe like. Those skilled in the art will recognize a wide variety ofnon-toxic pharmaceutically acceptable addition salts.

[0081] As used herein, the terms 2-benzothiazolyl and benzothiazol-2-ylare synonymous.

[0082] Representative groups of the formula

[0083] include those where J is oxygen and each r is 2 (morpholinyl), Jis nitrogen and each r is 2 (piperazinyl) or one r is 2 and the other 3(homopiperazinyl), or J is CH₂ and each r is 2 (piperidinyl) or one r is2 and the other 3 (homopiperidinyl). Preferred groups of this formulaare morpholinyl and piperazinyl.

[0084] The heterocyclic 5-membered ring having one to three nitrogenatoms, one of which may be replaced by oxygen or sulfur includesimidazolyl, oxazolyl, thiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl,and triazolyl.

[0085] The heterocyclic 6-membered ring having one to three nitrogenatoms, or one or two nitrogen atoms and one oxygen or sulfur includestriazinyl, pyrimidyl, pyridazinyl, oxazinyl and triazinyl.

[0086] The heterocyclic ring may be condensed with benzo so that saidring is attached at two neighboring carbon atoms to form a phenyl group.Such benzoheterocyclic ring may be attached to Z either through theheterocyclic group or through the benzo group of the benzoheterocyclicring. Specific wherein said heterocyclic ring is condensed with a benzoinclude benzoxazolyl, quinazolin-2-yl, 2-benzimidazolyl, quinazolin-4-yland benzothiazolyl. The oxazole or thiazole condensed with a 6-memberedaromatic group containing one or two nitrogen atoms include positionalisomers such as oxazolo[4,5-b]pyridine-2-yl,thiazolo[4,5-b]pyridine-2-yl, oxazolo[4,5-c]pyridine-2-yl,thiazolo[4,5-c]pyridine-2-yl, oxazolo[5,4-b]pyridine-2-yl,thiazolo[5,4-b]pyridine-2-yl, oxazolo[5,4-c]pyridine-2-yl, andthiazolo[5,4-c]pyridine-2-yl.

[0087] The following compounds of the invention are provided to give thereader an understanding of the compounds encompassed by the invention:

[0088] 3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-acetic acid

[0089]5-chloro-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-acetic acid

[0090]2-methyl-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-acetic acid

[0091]5-methyl-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-acetic acid

[0092]7-methyl-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-acetic acid

[0093]6-chloro-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-acetic acid

[0094]5-benzyloxy-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-aceticacid

[0095]6-fluoro-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-acetic acid

[0096]5-fluoro-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-acetic acid

[0097]6-methyl-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-acetic acid

[0098] 3-methyl(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-2propionic acid

[0099] 3-methyl(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-3propionic acid

[0100] 3-(5-trifluoromethylbenzothiazol-2-yl)methyl-indole-N-acetic acid

[0101]5-methyl-3-(5-trifluoromethylbenzothiazol-2-yl)methyl-indole-N-aceticacid

[0102] 3-(3-nitrophenyl)methyl-indole-N-acetic Acid

[0103] The above compounds, further described in the Examples and otherdescription of the invention below, are illustrative but are not meantto limit in any way the scope of the contemplated compounds according tothe present invention.

[0104] The compounds of general Formula I may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques. In addition, there isprovided a pharmaceutical formulation comprising a compound of generalFormula I and a pharmaceutically acceptable carrier. One or morecompounds of general Formula I may be present in association with one ormore non-toxic pharmaceutically acceptable carriers and/or diluentsand/or adjuvants and if desired other active ingredients. Thepharmaceutical compositions containing compounds of general Formula Imay be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsion, hard or soft capsules, or syrups or elixirs.

[0105] Compositions intended for oral use may be prepared according toany method known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed.

[0106] Formulations for oral use may also be presented as hard gelatincapsules wherein the active ingredient is mixed with an inert soliddiluent, for example, calcium carbonate, calcium phosphate or kaolin, oras soft gelatin capsules wherein the active ingredient is mixed withwater or an oil medium, for example peanut oil, liquid paraffin or oliveoil.

[0107] Aqueous suspensions contain the active materials in admixturewith excipients suitable for the manufacture of aqueous suspensions.Such excipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

[0108] Oily suspensions may be formulated by suspending the activeingredients in a vegetable oil, for example arachis oil, olive oil,sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.The oily suspensions may contain a thickening agent, for examplebeeswax, hard paraffin or cetyl alcohol. Sweetening agents such as thoseset forth above, and flavoring agents may be added to provide palatableoral preparations. These compositions may be preserved by the additionof an anti-oxidant such as ascorbic acid.

[0109] Dispersible powders and granules suitable for preparation of anaqueous suspension by the addition of water provide the activeingredient in admixture with a dispersing or wetting agent, suspendingagent and one or more preservatives. Suitable dispersing or wettingagents and suspending agents are exemplified by those already mentionedabove. Additional excipients, for example sweetening, flavoring andcoloring agents, may also be present.

[0110] Pharmaceutical compositions of the invention may also be in theform of oil-in-water emulsions. The oily phase may be a vegetable oil,for example olive oil or arachis oil, or a mineral oil, for exampleliquid paraffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,-anhydrides, for example sorbitan monoleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monoleate. The emulsions may also containsweetening and flavoring agents.

[0111] Syrups and elixirs may be formulated with sweetening agents, forexample glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, a preservative and flavoringand coloring agents. The pharmaceutical compositions may be in the formof a sterile injectable aqueous or oleaginous suspension. Thissuspension may be formulated according to the known art using thosesuitable dispersing or wetting agents and suspending agents which havebeen mentioned above. The sterile injectable preparation may also besterile injectable solution or suspension in a non-toxic parentallyacceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono-or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

[0112] The compounds of general Formula I may also be administered inthe form of suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

[0113] Compounds of general Formula I may be administered parenterallyin a sterile medium. The drug, depending on the vehicle andconcentration used, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

[0114] Dosage levels on the order of from about 0.1 mg to about 140 mgper kilogram of body weight per day are useful in the treatment of theabove-indicated conditions. (about 0.5 mg to about 7 g per patient perday). The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Dosageunit forms will generally contain between from about 1 mg to about 1000mg of an active ingredient.

[0115] It will be understood, however, that the specific dose level forany particular patient will depend upon a variety of factors includingthe activity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

[0116] The compounds of the present invention may be prepared by use ofknown chemical reactions and procedures. General methods forsynthesizing the compounds are presented below. It is understood thatthe nature of the substituents required for the desired target compoundoften determines the preferred method of synthesis. All variable groupsof these methods are as described in the generic description if they arenot specifically defined below. More detailed procedures for particularexamples are presented below in the experimental section.

[0117] Methods of Preparation

[0118] The compounds of the invention where Ar is benzothiazolyl can beconveniently prepared from a substituted indole moiety using generalScheme A set forth below.

[0119] Treatment of a nitrile indole IV with a strong base such as, forexample, sodium hydride, butyl lithium or sodium tert-butoxide, in apolar aprotic solvent such as acetonitrile, tetrahydrofuran orN,N-dimethylformamide followed by an treatment with an alkylating agent,e.g., ethyl or tert-butyl bromoacetate, provides the desired N-alkylatedproduct V. Alternativly, phase transfer catalysis can be used in abiphasic solvent system. A general review of such alkylations can befound in Sundberg, R. J. Indoles; Chapter 11, Academic Press Inc., SanDiego, Calif., 1996. Condensation with a suitable 2-amino thiophenolhydrochloride salt VI provides benzothiazole intermediate VII. Thesereactions are most often carried out in an alcohol solvents at elevatedtemperatures; however, other solvents like N,N-dimethylformamide andN-methylpyrrolidone can be used or the reactions can be carried out inthe absence of solvents altogether. The scope of the reaction conditionsuseful for this transformation have been described previously (U.S. Pat.No. 5,700,819). General methods for the preparation of varioussubstituted 2-amino thiophenols are also well known (J. Med. Chem. 1991,34, 108 and Chem. Pharm. Bull. 1994, 42, 1264). In general, the bestmethod of synthesis is determined by such factors as availability ofstarting materials and ease of synthesis. Deprotection of the alkanoicacid moiety VII can be carried out by methods common to those skilled inthe art to result in compounds of Formula III. The method used in thedeprotection depends on the type of protecting group. A description ofsuch protecting groups and methods for deprotecting them may be foundin: Protective Groups in Organic Synthesis, Second Edition, T. W. Greenand P. G. M. Wuts, John Wiley and Sons, Ney York, 1991. When a methyl orethyl ester is used, an aqueous sodium hydroxide solution in ethanol ordimethoxyethane is conveniently employed for its removal.

[0120] If not commercially available, nitrile IV can be preparedsubstantially as described below in Scheme B depicting the formation of3-acetonitrile substituted indoles of Formula IV where Z is a bond.Thus, an indole moiety in a weak acid solution, for example, acetic acidin ethanol, is treated with aqueous formaldehyde and dimethyl amine inan alcohol solvent. The 3-(dimethylamino)methyl indole product can thenbe treated with sodium or potassium cyanide in N,N-dimethylformamide atelevated temperatures to provide the 3-acetonitrile substituted indoleintermediate. Alternatively, an iminium salt likeN,N-dimethylmethyleneammonium chloride can be used to prepare the3-(dimethylamino)methyl indole intermediate.

[0121] The 3-(dimethylamino)methyl indole intermediate can also beconverted to the the 3-acetonitrile substituted indole intermediate viathe trimethyl ammonium salt. The salt can be prepared by treating thegramine intermediate with an alkalating agent like methyl iodide. Thetrimethyl ammonium salt intermediate can then be converted to thenitrile by treatment with sodium or potassium cyanide in a solvent likeN,N-dimethylformamide. In general, the conversion to the acetonitrileoccurs under more mild conditions when the trimethyl ammonium salt isused.

[0122] Alternatively, other compounds, such as those where Z-Arrepresents a wide variety of substituted hetercycles, may be preparedusing the general method outlined in Scheme C. Here, substituted indoleintermediates where X is an activating group like hydroxyl, halogen,dialkyl amino, trialkyl ammonium or benzotriazole are coupled withQ-Z-Ar groups using methods well-established in indole chemistry.Examples of these methods where Q is Na or H and Z is sulfur, oxygen,nitrogen carbon or a bond are described in (A) Tidwell, J. H.; Peat, A.J.; Buchwald, S. L. J. Org. Chem. 1994, 59, 7164; (B) Bruneau, P.;Delvare, C.; Edwards, M. P.; McMillan, R. M. J. Med. Chem. 1991, 34,1028; (C) Gan, T.; Cook, J. M. Tetrahedron Lett. 1997, 38, 1301; (D)Cerreto,F.; Villa, A.; Retico, A.; Scalzo, M. Eur. J. Med. Chem. 1992,27 701; (E) Majchrzak, M. W.; Zobel, J. N.; Obradovich, D. J.; Synth.Commun. 1997, 27, 3201; (F) DeLeon, C. Y.; Ganem, B. J. Org. Chem. 1996,61, 8730; (G) Katritzky, A. R.; Toader, D; Xie, L. J. Org. Chem. 1996,61, 7571.

[0123] It is understood that, depending on the specific chemistry used,a protecting group, P, may be required. In general, P represents groupssuch as acyloxy, alkyl, sulfonyl or A-COOR. The use of these generalmethods is illustrated in Protective Groups in Organic Synthesis, SecondEdition, T. W. Green and P. G. M. Wuts, John Wiley and Sons, Ney York,1991.

[0124] In general, the intermediate compounds wherein R₂₋₆ is aryl orheteroaryl can be synthesized by the chemistry illustrated in reactionScheme D below. For example, treatment of the potassium salt of anoptionally substituted bromoindole with tert-butyllithium at lowtemperature in an ethereal solvent such as ether or tetrahydrofuranfollowed by the addition of an electrophile represents a general methodfor obtaining substituted indoles, as described by Rapoport, H. (J. Org.Chem. 1986, 51, 5106). For a discussion of a synthesis where R is acyl,see Biorg. Med. Chem. Lett. 1999, 9, 333; where R is, thiomethyl, seeHeterocycles, 1992, 34, 1169; and where R is cycloalkyl, see J. Med.Chem. 1999, 42, 526.

[0125] More specifically the addition of a trialkyl borate followed byan acidic work-up provides the desired indole boronic acids(Heterocycles, 1992, 34, 1169). Indole boronic acids can be used in wellestablished transition metal catalyzed coupling reactions like theSuzuki reaction to provide aryl and heteroaryl indoles. These reactionsare most often carried out in a mixture of ethereal or alcohol solventswith aqueous base in the presence of palladium catalyst, such asPd(OAc)₂, Pd(OAc)₂ w/PPh₃ or Pd(PPh₃)₄ as described in Tetrahedron Lett.1998, 39, 4467, J. Org. Chem. 1999, 64, 1372 and Heterocycles 1992, 34,1395.

[0126] Alternatively, an optionally substituted bromoindole can betreated with an arylboronic acid and a palladium catalyst to providearylindoles in large quantities (Synlett 1994, 93). A general review ofSuzuki cross-couplings between boronic acids and aryl halides can befound in Miyaura, N; Suzuki, A. Chem. Rev. 1995, 95, 2457.

[0127] For example, treatment of the advanced intermediate indole X withan aryl or heteroaryl boronic acid using Pd-mediated coupling conditionsprovides the desired aryl and heteroaryl indole product XI as shown inscheme (E). In general the utility of this method is determined by theease of synthesis of advanced intermediates of type X and the commercialavailability of aryl and heteroaryl boronic acids.

[0128] In addition, certain organometallic reactions eliminate the needfor de novo construction of the indole nucleus. For example, the Stillereaction serves as a general method for the synthesis of regiocontrolledsubstitution of indole intermediates as described by Farina, V.;Krishnamurthy, V; Scott, W., Organic Reactions, 1998, 50, 1-652. Asindicated in the scheme below, the indole may serve as the organotinspecies or the aryl halide. The stannylindole (XII), where P is asuitable protecting group such as [2-(trimethyl)ethoxy]methyl (SEM) oran alkyl substituent, is treated with a variety of partners (i.e.,vinyl/allylic halides, vinyl triflates, aryl/heteroaryl halides and acylhalides) in the presence of a Pd(0)L_(n) catalyst to provide the desiredindoles (XII) (Synnlett 1993, 771, Helv. Chim. Acta 1993, 76, 2356 andJ. Org. Chem. 1994, 59, 4250). Conversely, a haloindole (XIV) is treatedwith a variety of tin reagents under Stille conditions to provide thedesired substituted indoles (XV) as described in Heterocycles 1988, 27,1585 and Synth. Comm 1992, 22, 1627).

[0129] A general procedure for the synthesis of intermediate compoundsusing amines of the formula NR_(x)R_(X2) (NR₁R₂ in the scheme below) isgiven in scheme F below. In Scheme F, R_(x) and R_(x2) are the same ordifferent and represent hydrogen, C₁-C₆ alkyl, or R_(x) and R_(x2)together represent a group of the formula:

[0130] where J and each r is as defined above for formula I.

[0131] As shown in Scheme F, nucleophilic substitution of X (X ishalogen, preferably fluorine) in an aromatic system is a method oftenused to substitute aromatic rings with amine and ether functionalities.Both 4- and 5-fluoro-2-nitrotoluene are sufficiently activated toundergo substitution with amines in the presence of K₂CO₃ in a polaraprotic solvent such as, for example, DMSO as described in J. Med. Chem.1993, 36, 2716. The Leimgruber-Batcho two-step method is a generalprocess for the construction of the indole ring system from theappropriate o-nitrotoluene. This reaction involves the condensation ofan o-nitrotoluene with N,N-dimethylformamide dimethyl acetal followed bya reductive cyclization under suitable conditions such as hydrogen overa palladium catalyst or Zn/HOAc as described in Sundberg, R. J. Indoles;Chapter 2, Academic Press Inc., San Diego, Calif., 1996. Arepresentative description of the process can also be found in OrganicSynthesis,. 1984, 63, 214.

[0132] A general procedure for the synthesis of intermediate compoundswherein R is an aromatic, heteroaromatic or alkyl group is indicated inScheme G below. As previously described, nucleophilic substitution ofhalogen, preferably fluorine, in an aromatic system is a method oftenused to substitute aromatic rings with amine and ether functionalities.Both 4- and 5-fluoro-2-nitrotoluene are sufficiently activated enough toundergo substitution with alcohols or phenols in the presence of K₂CO₃in a polar aprotic solvent such as DMSO. A similar system using KOH andphenol is described in J. Med. Chem. 1994, 37, 1955. Alternatively,solid-liquid phase transfer catalysis (PTC) methods have been used toprepare intermediate ethers of this type as described in Synth. Comm.1990, 20, 2855. The appropriately substituted o-nitrotoluene can then beconverted to the appropriate indole by the Leimgruber-Batcho methodpreviously desribed.

[0133] The preparation of intermediate alkoxy indole compounds wherein Ris C₁-C₆ alkyl is outlined in Scheme H below. Commercially availablenitrophenols can be alkylated under mild conditions with a base such as,for example, K₂CO₃ or Cs₂CO₃, in a polar aprotic solvent, e.g. CH₃CN,with a variety of suitable alkyl halides. See Synth. Comm. 1995, 25,1367. The alkoxy o-nitrotoluene can then be converted to the desiredindole as described above.

[0134] Alternatively, some examples of the invention where Z is a bondand Ar is a substituted heterocycle such as a thiazole; or Z is amideand Ar is a substituted phenyl can be conveniently prepared from anindole 3-acetic acid derivative as illustrated in Scheme I. Using thismethod, the carboxylic acid moiety is activated and coupled with an arylamine. Some examples of activating methods well-known to those skilledin the art include formation of acid chloride, mixed anhydrides andcoupling reagents such as 1,3-dicyclohexylcarbodiinide (DCC). A reviewof such method can be found in Bodanszky, M. Principles of PeptideSynthesis; Springer-Verlag: New York, 1984. For the examples where Z isa bond and Ar is a substituted benzothiazole or benzoxazole, theintermediate amide or thioamide can be cyclized into the aromatic ring.Examples of these types of hetercycle forming reactions are described inMylar, B. L. et al. J. Med. Chem. 1991, 34, 108. In addition, thecarboxylic acid can be converted to a chloro- or bromomethyl ketone andcondensed with nucleophiles like thioamides or 2-aminothiophenols toproduce thiazole or benzothiazine derivatives. Examples of methods toprepare the chloro- and bromomethyl ketones are illustrated in Rotella,D. P.; Tetrahedron Lett. 1995, 36, 5453 and Albeck, A.; Persky, R.;Tetrahedron 1994, 50, 6333. Depending on the reaction conditions in agiven synthetic sequence a protecting group may be required. It is alsounderstood that the specific order of steps used in the synthesisdepends on the particular example being prepared. P may represent H,A-COOH, A-COO-lower alkyl or a simple protecting group that can beremoved at a late stage of the synthesis. When such a protecting groupis used, the A-CO2R6 group can be introduced near the end of thesynthesis after the Z-Ar group has been assembled. Method of introducingthe Z-Ar group are similar to those already described.

[0135] Another strategy involves the synthesis of substituted indolesvia an intramolecular cyclization of an aniline nitrogen onto asubstituted alkyne as shown in Scheme J. Typical approaches utilizecommercially available o-iodoaniline derivatives. When theseintermediates are unavailable, the regioselective ortho iodination ofaromatic amines is used to generate the required intermediate (J. Org.Chem. 1996, 61, 5804). For example, Iodophenyl intermediates are treatedwith trimethylsilylacetylene in the presence of a Pd catalyst and aCu(I) source, such as cupric iodide, to produce o-alkynylanilines. SeeHeterocycles, 1996, 43, 2471 and J. Org. Chem. 1997, 62, 6507. Furtherelaboration of the o-alkynylaniline to the desired indole can be done bya copper-mediated cyclization or a base-induced amine ring closure ontothe alkyne functionality (J. Med. Chem. 1996, 39, 892). Alternativemodifications have been made in the acetylenic derivatives to generatemore elaborate indole structures as described in J. Am. Chem. Soc. 1991,113, 6689, Tetrahedron Lett. 1993, 24, 2823 and Tetrahedron Lett. 1993,34, 6471.

[0136] Those having skill in the art will recognize that the startingmaterials may be varied and additional steps employed to producecompounds encompassed by the present invention, as demonstrated by thefollowing examples. In some cases, protection of certain reactivefunctionalities may be necessary to achieve some of the abovetransformations. In general, the need for such protecting groups will beapparent to those skilled in the art of organic synthesis as well as theconditions necessary to attach and remove such groups.

[0137] The disclosures in this application of all articles andreferences, including patents, are incorporated herein by reference.

[0138] The preparation of the compounds of the present invention isillustrated further by the following examples, which are not to beconstrued as limiting the invention in scope or spirit to the specificprocedures and compounds described in them.

EXAMPLE 1 Preparation of2-methyl-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-acetic acid

[0139]

[0140]2-Methyl-3-(4,5,7-Trifluorobenzothiazol-2-yl)methyl-indole-N-acetic Acidwas prepared in a manner analogous to that set forth in Example 2,except 2-methylindole was used instead of 5-chloroindole in step 1:178-180° C.; ¹H NMR (DMSO-d₆, 300 MHz) δ 7.75-7.62 (m, 1 H), 7.45 (d,J=9.0 Hz, 1 H), 7.39 (d, J=9.0 Hz, 1 H), 7.08 (t, J=9 Hz, 1 H), 6.99 (t,J=9.0 Hz, 1 H), 5.00 (s, 2 H), 4.60 (s, 2 H), 2.38 (s, 3 H); LRMS calcdfor C₁₉H₁₃F₃N₂O₂S: 390.0; found 391.0 (M+1)⁺. Anal. Calcd forC₁₉H₁₃F₃N₂O₂S: C, 58.46; H, 3.36; N, 7.18; S, 8.21. Found: C, 58.47; H,3.29, N, 7.12, S, 8.18.

EXAMPLE 2 Preparation of5-chloro-3-(4,5,7-Trifluorobenzothiazol-2-yl)methyl-indole-N-acetic Acid

[0141]

5-chloroindole-3-acetonitrile

[0142] A solution of aqueous formaldehyde (37%, 2.95 mL, 66.0 mmol) anddimethylamine (40%, 5.30 mL, 66.0 mmol) in 20 mL EtOH was cooled to 0°C. 5-Chloroindole (4.0 g, 26.4 mmol) was dissolved in a HOAc:EtOHmixture (1:1, 40 mL) and added dropwise to the reaction mixture. Afterstirring at this temperature for 2 h, the mixture was allowed to warm toroom temperature and stir overnight. The mixture was added to a sat'dsolution of NaHCO₃. 1 N NaOH was added until the pH was between 9-10.The resulting mixture was extracted with CH₂Cl₂ (3×). The organics werecombined and washed with a sat'd aq. NaCl, dried over MgSO₄, filteredand concentrated in vacuo to give 4.65 g (85%) of5-chloro-3-[(dimethylamino)methyl] indole as a yellow powder. Withoutfurther purification, 5-chloro-3-[(dimethylamino)methyl] indole (4.65 g,22.4 mmol) was dissolved in dimethylformamide (80 mL) at roomtemperature with stirring. To this was added KCN (2.18 g, 33.5 mmol) inH₂O (10 mL). The mixture was warmed to 140° C. and stirred for 14 h. H₂Owas added and the mixture was extracted with EtOAc (2×). The organicswere combined and washed with sat'd brine, dried over MgSO₄, filteredand concentrated in vacuo. The residue was purified by SiO₂ flashchromatography (3:2, Heptane: EtOAc) to give 2.65 g (63%) of5-chloroindole-3-acetonitrile. ¹H NMR (DMSO-d₆, 300 MHz) δ 11.30 (br s,1 H), 7.63 (s, 1 H), 7.42-7.38 (m, 2 H), 7.05 (d, J=6.0 Hz, 1 H), 5.70(s, 2 H),

5-chloro-3-(4,5.7-trifluorobenzothiazol-2-yl)methyl-indole-N-acetic acid

[0143]5-chloro-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-acetic acidwas prepared in a manner analogous to that set forth in Example 3 (steps1-7), except 5-chloroindole-3-acetonitrile was used instead of 3-indolylacetonitrile in step 5: mp 188-189° C.; ¹H NMR (DMSO-d₆, 300 MHz)7.73-7.68 (m, 1 H), 7.63 (d, J=1.8 Hz, 1 H), 7.51 (s, 1 H), 7.45 (d,J=9.0 Hz, 1 H), 7.14 (dd, J₁=9.0, J₂=2.4 Hz, 1 H), 5.04 (s, 2 H), 4.65(s, 2 H); LRMS calcd for C₁₈H₁₀F₃N₂O₂SCl: 410.0; found 411.0 (M+1)⁺.Anal. Calcd for C₁₈H₁₀F₃N₂O₂SCl: C, 52.63; H, 2.45; N, 6.82; S, 7.81.Found: C, 52.56; H, 2.40, N, 6.71, S, 7.72.

EXAMPLE 3 Preparation of3-(4,5,7-Trifluorobenzothiazol-2-yl)methyl-indole-N-acetic Acid

[0144]

2,3,5,6-Tetrafluoroacetanilide

[0145] A solution of 2,3,5,6-tetrofluoroaniline (200 g, 1.21 mol) inanhydrous pyridine (103 mL, 1.27 mol) was treated with acetic anhydride(120 mL, 1.27 mol) and heated to 120° C. for 2 h. After cooling to roomtemperature, the solution was poured into ice-cold water (500 mL). Theresulting precipitate was filtered, dissolved in ethyl acetate, driedover MgSO₄, filtered and concentrated. The solid material was washedwith heptane (200 mL) and dried to give 2,3,5,6-tetrafluoroacetanilideas a white crystalline solid (206 g, 82%): mp 136-137° C.; R_(f) 0.48(50% ethyl acetate in heptane); ¹H NMR (DMSO-d₆, 300 MHz) δ 10.10 (s, 1H), 7.87-7.74 (m, 1 H), 2.09 (s, 3 H). Anal. Calcd for C₈H₅F₄NO: C,46.39; H, 2.43; N, 6.67. Found C, 46.35; H, 2.39; N, 6.68.

2,3,5,6-Tetrafluorothioacetanilide

[0146] A flame-dried, 4-necked 5,000 mL round-bottomed flask was chargedwith phosphorous pentasulfide (198 g, 0.45 mol) and diluted withanhydrous benzene (3,000 mL, 0.04 M). 2,3,5,6-tetrafluoroacetanilide(185 g, 0.89 mol) was added in one portion and the bright yellowsuspension was heated to a gentle reflux for 3 h. The solution wascooled to 0° C. and filtered. The insoluble material was washed withether (2×250 mL) and the combined filtrate was extracted with 10% aq.NaOH (750 mL, 500 mL). After cooling the aqueous layer to 0° C., it wascarefully acidified with conc. HCl (pH 2-3). The precipitated productwas collected by filtration and washed with water (500 mL). Theyellow-orange material was disolved in ethyl acetate (1,000 mL), driedover MgSO₄ and activated charcoal (3 g), filtered through a sh

t pad of silica (50 g), and concentrated. The resulting solid wastriturated with heptane (500 mL) and filtered to give2,3,5,6-tetrafluorothioacetanilide (174.9 g, 88%): mp: 103-104° C.;R_(f) 0.67 (50% ethyl acetate in heptane); ¹H NMR (DMSO-d_(6,) 300 MHz)δ 11.20 (s, 1 H), 8.00-7.88 (m, 1 H), 2.66 (s, 3 H). Anal. Calcd forC₈H₅F₄NS: C, 43.05; H, 2.26; N, 6.28. Found C, 43.10; H, 2.23; N, 6.19.

4,5,7-Trifluoro-2-methylbenzothiazole

[0147] A flame-dried 5,000 mL round-bottomed flask equipped withover-head stirrer was charged with sodium hydride (15.9 g, 0.66 mol) anddiluted with anhydrous toluene (3,000 mL, 0.2 M). The suspension wascooled to 0° C., and treated with 2,3,5,6-tetrafluorothioacetanilide(134 g, 0.60 mol) in one portion. The solution was warmed to roomtemperature over 1 h, then heated to a gentle reflux. After 30 min,dimethylformamide (400 mL) was carefully added and the mixture wasstirred for an additional 2 h. The solution was cooled to 0° C. andadded to ice-water (2,000 mL). The solution was extracted with ethylacetate (1,500 mL) and washed with sat'd. aq. NaCl (1,000 mL). Theorganic layer was concentrated to dryness, diluted with heptane andsuccessively washed with water (300 mL) and sat'd. aq. NaCl (1,000 mL).The organic layer was dried over MgSO₄, filtered and concentrated togive 4,5,7-trifluoro-2-methylbenzothiazole (116.8 g, 96%) as a lightbrown solid: mp: 91-92° C.; R_(f) 0.56 (30% ethyl acetate in heptane);¹H NMR (DMSO-d₆, 300 MHz) δ 7.76-7.67 (m, 1 H), 2.87 (s, 3 H); Anal.Calcd for C₈H₄F₃NS: C, 47.29; H, 1.98; N, 6.82; S, 15.78. Found C,47.56; H, 2.07; N, 6.82; S, 15.59.

2-Amino-3,4,6-trifluorothiophenol Hydrochloride

[0148] A solution of 4,5,7-trifluoro-2-methylbenzothiazole (25.0 g, 123mmol) in ethylene glycol (310 mL, 0.4 M) and 30% aq. NaOH (310 mL, 0.4M) was degassed using a nitrogen stream then heated to a gentle reflux(125° C.) for 3 h. The solution was cooled to 0° C. and acidified to pH3-4 using conc. HCl (appox. 200 mL). The solution was extracted withether (750 mL) and washed with water (200 mL). The organic layer wasdried over Na₂SO₄, filtered and treated with2,2-di-tert-butyl-4-methylphenol (0.135 g, 0.5 mol %). Afterconcentrating to dryness, the crude product was dissolved in anhydrousmethanol (200 mL) and treated with an HCl solution in 1,4-dioxane (37mL, 4 N, 148 mmol). The resulting mixture was concentrated to dryness,triturated with isopropylether (100 mL) and filtered to give2-amino-3,4,6-trifluorothiophenol hydrochloride (19.3 g, 73%) as a lightbrown solid that was used without further purification. mp. 121-124 C;R_(f) 0.43 (30% ethyl acetate in heptane); Anal. Calcd for C₆H₅ClF₃NS:C, 33.42; H, 2.34; N, 6.50; S, 14.87. Found C, 33.45; H, 2.27; N, 6.48;S, 14.96.

3-cyanomethyl-indole-N-acetic acid, Ethyl Ester

[0149] Under an atmosphere of nitrogen, a solution of 3-indolylacetonitrile (25.0 g, 160 mmol) in dry acetonitrile (530 mL, 0.3 M) wastreated with sodium hydride (95%, 4.2 g, 168 mmol) and stirred for 30min. Ethyl bromoacetate (21.3 mL, 192 mmol) was added in a dropwisemanner over 10 min and the solution was stirred at room temperature for16 h. After concentrating under reduced pressure, the resulting residuewas dissolved in ethyl acetate and washed with sat'd. aq. NaCl. Theorganic extracts were dried over MgSO₄, filtered and concentrated. Thecrude product was recrystalized from heptane and ethyl acetate to givethe target compound as a white crystalline solid (19 g, 49%): mp 98-99°C.; R_(f) 0.29 (30% ethyl acetate in heptane); ¹H NMR (DMSO-d₆, 300 MHz)δ 7.59 (dd, J₁=7.8 Hz, J₂=0.6 Hz, 1 H), 7.40 (dd, J₁=8.1 Hz, J₂=0.6 Hz,1 H), 7.36 (s, 1 H), 7.18 (b t, J=7.2 Hz, 1 H), 7.10 (b t, J=7.2 Hz, 1H), 5.12 (s, 2 H), 4.14 (q, J=7.2 Hz, 2 H), 4.06, (s, 2 H), 1.20 (t,J=7.2 Hz, 3 H); ); LRMS calcd for C₁₄H₁₄N₂O₂:242.3; found 243.0 (M+1)⁺.Anal. Calcd for C₁₄H₁₄N₂O₂: C, 69.49; H, 5.82; N, 11.56. Found C, 69.39;H, 5.89; N, 11.59.

3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-acetic acid, EthylEster

[0150] Under a nitrogen atmosphere, a solution of3-acetonitrile-indole-N-acetic acid, ethyl ester (11.0 g, 45.4 mmol) inanhydrous ethanol (90 mL, 0.5 M) was treated with2-amino-3,4,6-trifluorothiophenol hydrochloride (12.7 g, 59.0 mmol) andheated to a gentle reflux for 16 h. After cooling to room temperature,the solution was concentrated under reduced pressure, diluted with ethylacetate and washed with 2N HCl and sat'd. aq. NaCl. The organic layerwas dried over MgSO₄, filtered and concentrated. Purification by MPLC(10-50% ethyl acetate in heptane, 23 mL/min, 150 min) to give3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-acetic acid, ethylester (6.0 g, 36%) as a white crystalline solid: mp 110-111° C.; R_(f)0.41 (30% ethyl acetate in heptane); ¹H NMR (DMSO-d₆ 300 MHz) δ7.74-7.66 (m, 1 H), 7.54 (d, J=7.8 Hz, 1 H), 7.46 (s, 1 H), 7.40 (d,J=8.1 Hz, 1 H), 7.15 (br t, J=6.9 Hz, 1 H), 7.04 (br t, J=7.8 Hz, 1 H),5.14, s, 2 H), 4.66 (s, 2 H), 4.14 (q, J=7.2 Hz, 3 H); LRMS calcd forC₂₀H₁₅F₃N₂O₂S: 404.4; found 405.0 (M+1)⁺. Anal. Calcd for C₂₀H₁₅F₃N₂O₂S;C, 59.40; H, 3.74; N, 6.93; S, 7.93. Found C, 59.52; H, 3.721 N, 6.92;S, 8.04.

3-(4,5,7-trifluorobenzothiazol-2yl)methyl-indole-N-acetic acid

[0151] A solution of give3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-acetic acid, ethylester (5.91 g, 14.6 mmol) in 1,2-dimethoxyethane (73 mL, 0.2 M) wascooled to 0° C. and treated with aq. NaOH (1.25 N, 58 mL, 73.1 mmol) ina dropwise manner over 15 min. After the addition was complete, thesolution was stirred for an additional 30 min, acidified to pH 3 with 2NHCl, and concentrated under reduced pressure. The residue was dissolvedin ethyl acetate (200 mL) and washed with sat'd. aq. NaCl (30 mL). Theorganic extract was dried over Na₂SO₄, filtered and concentrated. Theresulting material was stirred as a supension in heptane, filtered anddried to give 3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-aceticacid (5.38 g, 98%) as a pale yellow solid: mp 177-178° C.; R_(f) 0.44(20% methanol in dichloromethane); ¹H NMR (DMSO-d₆, 300 MHz) δ 7.74-7.65(m, 1 H), 7.53 (d, J=7.5 Hz, 1 H), 7.46 (s, 1 H), 7.40 (d, J=8.1 Hz, 1H), 7.15 (b t, J=6.9 Hz, 1 H), 7.03 (b t, J=7.2 Hz, 1 H), 5.03 (s, 2 H),4.65 (s, 2 H); LRMS calcd for C₁₈H₁₁F₃N₂O₂S: 376.4; found 375.0 (M−1)⁻.Anal. Calcd for C₁₈H₁₁F₃N₂O₂S: C, 57.44; H, 2.95; N, 7.44; S, 8.52.Found C, 57.58; H, 2.99; N, 7.38; S, 8.51.

EXAMPLE 4 Preparation of5-methyl-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-acetic acid

[0152]

[0153]5-Methyl-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-acetic Acidwas prepared in a manner analogous to that set forth in Example 2,except 5-methylindole was used instead of 5-chloroindole in step 1: mp131-133° C.; ¹H NMR (DMSO-d₆, 300 MHz) δ 7.73-7.62 (m, 1 H), 7.39 (s, 1H), 7.30 (s, 1 H), 7.27 (d, J=9.0 Hz, 1 H), 6.96 (dd, J₁=9.0 Hz, J₂=2.4Hz, 1 H), 4.98 (s, 2 H), 4.60 (s, 2 H), 2.32 (s, 3 H); LRMS calcd forC₁₉H₁₃F₃N₂O₂S: 390.0; found 391.0 (M+1)⁺. Anal. Calcd for C₁₉H₁₃F₃N₂O₂S:C, 58.46; H, 3.36; N, 7.18; S, 8.21. Found: C, 58.36; H, 3.30, N, 7.10,S, 8.20.

EXAMPLE 5 Preparation of7-methyl-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-acetic acid

[0154]7-Methyl-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-acetic Acidwas prepared in a manner analogous to that set forth in Example 2,except 7-methylindole was used instead of 5-chloroindole in step 1: mp216-218° C.; ¹H NMR (DMSO-d₆, 300 MHz) δ 7.73-7.63 (m, 1H), 7.36-7.32(m, 2 H), 6.92-6.88 (m, 2 H), 5.17 (s, 2 H), 4.60 (s, 2 H), 2.55 (s, 3H); LRMS calcd for C₁₉H₁₃F₃N₂O₂S: 390.0; found 391.0 (M+1)⁺. Anal. Calcdfor C₁₉H₁₃F₃N₂O₂S: C, 58.46; H, 3.36; N, 7.18; S, 8.21. Found: C, 58.37;H, 3.37; N, 7.11; S, 8.13.

EXAMPLE 6 Preparation of6-chloro-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-acetic acid

[0155]6-Chloro-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-acetic Acidwas prepared in a manner analogous to that set forth in Example 2,except 6-chlorolindole was used instead of 5-chloroindole in step 1: mp194-195° C.; ¹H NMR (DMSO-d₆, 300 MHz) δ 7.73-7.63 (m, 1 H), 7.50 (d,J=8.4 Hz, 1 H), 7.46-7.42 (m, 2 H), 7.00 (dd, J₁=8.4 Hz, J₂=2.1 Hz, 1H), 4.76 (s, 2 H), 4.62 (s, 2 H); LRMS calcd for C₁₈H₁₀F₃N₂O₂SCl: 410.0;found 411.0 (M+1)⁺. Analysis calculated for C₁₈H₁₀F₃N₂O₂SCl: C, 52.63;H, 2.45; N, 6.82; S, 7.81. Found: C, 52.50; H, 2.44, N, 6.74, S, 7.69.

EXAMPLE 7 Preparation of5-benzyloxy-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-aceticacid

[0156]

[0157]5-Benzyloxy-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-aceticAcid was prepared in a manner analogous to that set forth in Example 2,except 5-benzyloxyindole was used instead of 5-chloroindole in step 1:mp 165-168° C.; ¹H NMR (DMSO-d₆, 300 MHz) δ 7.73-7.65 (m, 1 H) 7.40-7.30(m, 3 H), 7.28-7.10 (m, 4 H), 7.10 (d, J=2.4 Hz, 1 H), 6.87-6.80 (m, 1H), 5.05 (s, 2 H), 4.95 (s, 2 H), 4.57 (s 2 H); LRMS calcd forC₂₅H₁₇F₃N₂O₂S: 482.0; found 483.0 (M+1)⁺.

EXAMPLE 8 Preparation of6-fluoro-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-acetic acid

[0158]6-fluoro-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-acetic Acidwas prepared in a manner analogous to that set forth in Example 2,except 6-fluoroindole was used instead of 5-chloroindole in step 1: mp200-203° C.; ¹H NMR (DMSO-d₆, 300 MHz) δ 7.73-7.65 (m, 1 H), 7.53 (dd,J₁=8.4 Hz, J₂=3.3 Hz, 1 H), 7.44 (s, 1 H), 7.34 (dd, J₁=10.5 Hz, J₂=2.4Hz, 1 H), 6.93-6.68 (m, 1 H), 5.11 (s, 2 H), 4.64 (s, 2 H); LRMS calcdfor C₁₈H₁₀F₄N₂O₂S: 394.0; found 395 (M+1).

EXAMPLE 9 Preparation of5-fluoro-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-acetic acid

[0159]

[0160]5-fluoro-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-acetic Acidwas prepared in a manner analogous to that set forth in Example 2,except 5-fluoroindole was used instead of 5-chloroindole in step 1: mp193-195° C.; ¹H NMR (DMSO-d₆, 300 MHz) δ 7.65 (m, 1 H), 7.51 (s, 1 H),7.42 (br dd, J₁=9.0 Hz, J₂=4.8 Hz, 1 H), 7.34 (br dd, J₁=9.9 Hz, J₂=2.4Hz, 1 H), 7.02-6.96 (m, 1 H), 5.03 (s, 2 H), 4.62 (s, 2 H); LRMS calcdfor C₁₈H₁₀F₄N₂O₂S: 394.0; found 395 (M+1).

EXAMPLE 10 Preparation of6-methyl-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-acetic acid

[0161]6-methyl-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-acetic Acidwas prepared in a manner analogous to that set forth in Example 2,except 6-methylindole was used instead of 5-chloroindole in step 1: mp211-213° C., R_(f)0.50 (10% methanol in diehloromethane); ¹H NMR(DMSO-d₆, 300 MHz) 7.72-7.63 m, 1 H), 7.37 (d, J=7.1 Hz, 1 H), 7.35 (s,1 H), 7.18 (s, 1 H), 6.85 (d, J=8.4 Hz, 1 H), 5.08 (s, 2 H), 4.60 (s, 2H), 2.37 (s, 3 H).

EXAMPLE 11 Preparation of3-(5-trifluoromethylbenzothiazol-2-yl)methyl-indole-N-acetic Acid

[0162] 3-(5-trifluoromethylbenzothiazol-2-yl)methyl-indole-N-acetic Acidwas prepared in a manner analogous to that set forth in Example 3 (steps5-7), except 2-amino-4-(trifluoromethyl)-benzenethiol hydrochloride wasused instead of 2-amino-3,4,6-trifluorothiophenol hydrochloride in step6:

[0163] mp 233-234° C.; ¹H NMR (DMSO-d₆, 300 MHz) δ 8.29 (s, 1 H), 8.19(br d, J=8.1 Hz, 1 H), 7.68 (br d, J=9.0 Hz, 1 H), 7.49 (br d, J=6.9 Hz,1 H), 7.41 (s, 1 H), 7.38 (br d, J=8.4 Hz, 1 H), 7.12 (br t, J=6.9 Hz, 1H), 7.00 (br t, J=6.9 Hz, 1 H), 5.01 (s, 2 H), 4.60 (s, 2 H).

EXAMPLE 12 Preparation of5-Methyl-3-(5-Trifluoromethylbenzothiazol-2-yl)methyl-indole-N-aceticacid

[0164]5-Methyl-3-(5-trifluoromethylbenzothiazol-2-yl)methyl-indole-N-aceticacid was prepared in a manner analogous to that set forth in Example 2,except 5-methylindole was used instead of 5-chloroindole in step 1 and,2-amino-4-(trifluoromethyl)-benzenethiol hydrochloride was used insteadof 2-amino-3,4,6-trifluorothiophenol hydrochloride in step 2 (Example 3,step 6): mp 248-249° C.; ¹H NMR (DMSO-d₆, 300 MHz) δ 8.27 (s, 1 H), 8.20(d, J=8.4 Hz, 1 H), 7.68 (d, J=8.4 Hz, 1 H), 7.35 (s, 1 H), 7.27 (s, 1H), 7.25 (d, J=8.1 Hz, 1 H), 6.95 (d, J=8.1 Hz, 1 H), 4.96 (s, 2 H),4.57 (s, 2 H), 2.31, (s, 3 H); LRMS calcd for C₂₀H₁₅F₃N₂O₂S:; found 405(M+H).

EXAMPLE 13 Preparation of 3-(3-nitrophenyl)methyl-indole-N-acetic acid

[0165]

Preparation of indole-N-acetic acid, ethyl ester

[0166] Under an atmosphere of nitrogen, a solution of indole (15.0 g,128 mmol) in dry acetonitrile (300 mL, 0.4 M) was treated with sodiumhydride (95%, 3.69 g, 153 mmol) and stirred for 30 min. Ethylbromoacetate (17.0 mL, 153 mmol) was added in a dropwise manner over 10min and the solution was stirred at room temperature for 16 h. Afterconcentrating under reduced pressure, the resulting residue wasdissolved in ethyl acetate and washed with sat'd. aq. NaCl. The organicextracts were dried over MgSO₄, filtered and concentrated. The crudeproduct was purified by flash column chromatography (50% ethyl acetatein heptane): Rf0.25 (40% ethyl acetate in heptane) ¹H NMR (DMSO-d₆, 300MHz) δ 7.53 (d, J=6.3 Hz, 1 H), 7.38-7.31 (m, 2 H), 7.11 (br t, J=7.2Hz, 1 H), 7.02 (br t, J=7.2 Hz, 1 H), 6.45-6.43 (m, 1 H), 5.10 (s, 2 H),4.12 (q, J=7.2 Hz, 2 H), 1.19 (t, J=7.2 Hz, 3 H).

Preparation of 3-(3-nitrophenyl)methyl-indole-N-acetic acid, ethyl ester

[0167] Indole-N-acetic acid, ethyl ester (0.500 g, 2.50 mmol) wasdissolved in 1,4-dioxane (5 mL) at room temperature with stirring. Tothis solution was added Ag₂Co₃/Celite (50% by weight, 0.500 g, 0.9mmol). The mixture was warmed to 90° C. and maintained overnight. H₂Owas added to the reaction mixture followed by extracted with EtOAc (2×).The organics were combined and washed with a sat'd brine solution, driedover MgSO₄, filtered and concentrated in vacuo. The residue was purifiedby SiO₂ flash chromatography (3:2 Heptane: EtOAc) to give 180 mg (22%)as a pale yellow oil. ¹H NMR (DMSO-d₆, 300 MHz) δ 8.10 (s, 1H), 8.02 (d,J=8.1 Hz, 1 H), 7.75 (d, J=7.2 Hz, 1 H), 7.59-7.57 (m, 1 H), 7.46-7.39(m, 1 H), 7.33 (d, J=8.1 Hz, 1 H), 7.20 (s, 1 H), 7.13-6.89 (m, 2 H),5.06 (s, 2 H), 4.19 (s, 2 H), 4.13 (q, J=7.2 Hz, 2 H), 1.18 (t, J=7.2Hz, 3 H).

Preparation of 3-(3-nitrophenyl)methyl-indole-N-acetic Acid

[0168] 3-(3-Nitrophenyl)methyl-indole-N-acetic Acid, ethyl ester (0.175g, 0.5 mmol) was dissolved in THF:EtOH (1:4, 5 mL) at room temperaturewith stirring. The mixture was cooled to 0° C. and treated with 1N NaOH(1.55 mL, 1.6 mmol). The mixture was allowed to stir at this temperaturefor 2 h. 1 N HCl was added and the mixture extracted with EtOAc (2×).The organics were combined and washed with a sat'd brine solution, driedover MgSO₄, filtered and concentrated in vacuo. The residue wastriturated with heptane and vacuum-filtered with several heptanewashings to give 110 mg (69%) the desired compound as an off-whitepowder. mp 163-165° C.; ¹H NMR (DMSO-d₆, 300 MHz) δ 8.11 (s, 1 H), 8.03(d, J=8.1 Hz, 1 H), 7.75 (d, J=8.1 Hz, 1 H), 7.53 (t, J=8.1 Hz, 1 H),7.45 (d, J=8.1 Hz, 1 H), 7.33 (d, J=8.4 Hz, 1 H), 7.20 (s, 1 H), 7.11(t, J=7.2 Hz, 1 H), 6.97 (t, J=7.2 Hz, 1 H), 4.96 (s, 2 H), 4.18 (s, 2H); LRMS calcd for C₁₇H₁₄N₂O₄S: 310.0; found 311 (M+1)⁺.

EXAMPLE 14 Preparation of2-phenyl-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-acetic acid

[0169]

[0170]2-phenyl-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-acetic acidwas prepared in a manner analogous to that set forth in Example 2,except that 2-phenylindole was used instead of 5-chloroindole in step 1:mp 238-239° C.; R_(f) 0.60 (10% methanol in chloroform); ¹H NMR(DMSO-d₆, 300 MHz) δ 7.60-7.70 (m, 1H), 7.39-7.58 (m, 7H), 7.20 (t, J=9Hz, 1H), 7.07 (t, J=9 Hz, 1H), 4.80 (s, 2H), 4.45 (s, 2H); LRMS calcdfor C₂₄H₁₅F₃N₂O₂S: 452.0; found 453.0 (M+1)⁺. Anal. Calcd forC₂₄H₁₅F₃N₂O₂S: C, 63.71; H, 3.34; N, 6.19; S, 7.09. Found: C, 63.46; H,3.32; N, 6.11; S, 6.96.

EXAMPLE 15 Preparation of5-phenyl-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-acetic acid3-cyanomethyl-5-phenyl-indole-N-acetic acid, ethyl ester

[0171] 5-Bromo-3-cyanomethyl-indole-N-acetic acid, ethyl ester (1.0 g,3.1 mmol) and phenylboronic acid (0.418 g, 3.4 mmol) were dissolved inanhydrous DME at room temperature under a nitrogen atmsophere andtreated with Pd(OAc)₂ (2.1 mg, 0.0093 mmol) and PPh₃ (7.4 mg, 0.028mmol). This mixture was heated to reflux and 2 M Na₂CO₃ (3.11 mL, 6.2mmol) was added via syringe. After 12 h, the mixture was cooled to roomtemperature and added to H₂O (50 mL). The resultant mixture wasextracted with EtOAc (2×, 100 mL) and the organics were combined andwashed with a sat'd aqueous NaCl solution, dried over MgSO₄, filteredand concentrated in vacuo. The residue was purified by SiO₂ flashchromatography (heptane to 1:1 heptane/EtOAc) to give the desiredmaterial as a white solid (445 mg, 45%); ¹H NMR (DMSO-d₆, 300 MHz) δ7.64-7.74 (m, 4H), 7.39-7.44 (m, 4H), 7.29-7.34 (m, 1H), 5.20 (s, 2H),4.15 (q, J=7.2 Hz, 2H), 4.08 (s, 2H), 1.20 (t, J=7.2 Hz, 3H).

5-phenyl-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl indole-N-acetic acid

[0172]5-phenyl-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-acetic acidwas prepared in a manner analogous to that set forth in Example 2,except that 5-phenylindole was used instead of 5-chloroindole in step 1:mp 156-159° C.; R_(f) 0.55 (10% methanol in chloroform); ¹H NMR(DMSO-d₆, 300 MHz) δ 7.66-7.69 (m, 4H), 7.57-7.60 (m, 1H), 7.39-7.47 (m,3H), 7.29-7.35 (m, 2H), 5.06 (s, 2H), 4.66 (s, 2H); LRMS calcd forC₂₄H₁₅F₃N₂O₂S: 452.0; found 453.0 (M+1)⁺. Anal. Calcd for C₂₄H₁₅F₃N₂O₂S:C, 63.71; H, 3.34; N, 6.19; S, 7.09. Found: C, 63.54; H, 3.32; N, 6.13;S, 7.01.

EXAMPLE 16 Preparation of6-phenyl-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-acetic acidStep 1: 6-Phenylindole

[0173] A solution of 6-bromoindole (2.0 g, 10.20 mmol) in anhydroustoluene (20 mL) under a nitrogen atmosphere was treated with Pd[P(Ph₃)]₄(10% mol). After stirring the mixture for 30 min., phenylboronic acid(1.87 g, 15.30 mmol) in anhydrous EtOH (10 mL) was added followed by theaddition of sat'd NaHCO₃ (6 mL). The bi-phasic mixture was heated toreflux for 24 h. After cooling to room temperature, the mixture wasadded to a sat'd brine solution and extracted with EtOAc (2×). Theorganic layer was dried over MgSO₄, filtered and concentrated in vacuo.The residue was purified by flash column chromatography (1:1CH₂Cl₂/heptane) to give the desired material as white powder (900 mg,45%): ¹H NMR (DMSO-d₆, 300 MHz) δ 11.15 (br s, 1H), 7.58-7.66 (m, 4H),7.41-7.47 (m, 2H), 7.36 (m, 1H), 7.26-7.31 (m, 2H), 6.42 (m, 1H).

[0174] Preparation of6-phenyl-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl indole-N-acetic acid6-phenyl-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-acetic acidwas prepared in a manner analogous to that set forth in Example 2,except that 6-phenylindole was used instead of 5-chloroindole in step 1:mp 156-159° C.; R_(f) 0.50 (10% methanol in chloroform);

[0175]¹H NMR (DMSO-d₆, 300 MHz) δ 7.65-7.75 (m, 4H), 7.57-7.62 (m, 1H),7.41-7.50 (m, 3H), 7.26-7.38 (m, 2H), 5.12 (s, 2H), 4.68 (s, 2H); LRMScalcd for C₂₄H₁₅F₃N₂O₂S: 452.0; found 453.0 (M+1)⁺. Anal. Calcd forC₂₄H₁₅F₃N₂O₂S: C, 63.71; H, 3.34; N, 6.19; S, 7.09. Found: C, 63.46; H,3.33; N. 6.10; S, 6.96.

EXAMPLE 17 Preparation of5-morpholino-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-aceticacid

[0176]

5-Morpholino-2-nitrotoluene

[0177] A mixture of 5-fluoro-2-nitrotoluene (5.11 g, 32.9 mmol),morpholine (4.31 mL, 49.4-mol) and K₂CO₃ (6.83 g, 49.4 mmol) was dilutedin anhydrous DMSO (80 mL) at room temperature with stirring. The mixturewas heated to 80° C. for 24 h. After cooling to room temperature, H₂Owas added and the resultant mixture was extracted with EtOAc (3×, 50mL). The organic layer was washed with sat'd aqueous NaCl (100 mL),dried over MgSO₄, filtered and concentrated in vacuo. The remainingsolid was triturated in heptane (200 mL) and filtered to give thedesired material (7.10 g, 97%) as a yellow powder: R_(f) 0.40 (75%heptane/25% ethyl acetate). ¹H NMR (DMSO-d₆, 300 MHz) δ 7.96 (d, J=9.9Hz, 1H), 8.85-8.88 (m, 2H), 3.70 (t, J=5.0 Hz, 4H), 3.35 (t, J=5.0 Hz,4H), 2.53 (s, 3H).

Preparation of 5-Morpholinoindole

[0178] Under an atmosphere of nitrogen, a solution of5-morpholinyl-2-nitrotoluene (7.0 g, 31.5 mmol) in DMF (100 mL) wastreated with dimethylformamide dimethyl acetal (4.81 mL, 36.2 mmol) andpyrrolidine (2.62 mL, 31.5 mL). The mixture was heated to 100° C. andmaintained for 12 h. After cooling, the mixutre was concentrated invacuo to give the desired intermediate as a brick-red solid.

[0179] The intermediate enamine was dissolved in EtOAc (200 mL) andadded to a pre-charged Parr bottle with 10% Pd/C (600 mg) in EtOAc (40mL). The mixture was hydrogentated on a Parr-shaker at 55 psi for 2.5 h.The catalyst was filtered through a Celite plug with several washingswith EtOAc and the remaining filtrate concentrated in vacuo. The residuewas purified by SiO₂ flash chromatography (1:1 Hept/EtOAc) to give 2.0 g(31% over 2 steps) of the desired indole as a cream powder: R_(f) 0.30(10% methanol in chloroform); ¹H NMR (DMSO-d₆, 300 MHz) δ 10.77 (br s,1H), 7.24 (s, 1H), 7.18-7.20 (m, 1H), 6.97 (d, J=1.8 Hz, 1H), 6.81 (dd,J₁=8.7 Hz, J₂=2.1 Hz, 1H), 6.25 (dd, J₁=3.0 Hz, J₂=1.8 Hz, 1H), 3.7 (t,J=4.50 Hz, 4H), 2.96 (t, J=4.50 Hz, 4H).

Preparation of 5-morpholino-3(4,5,7-trifluorobenzothiazol-2-yl)methylindole-N-acetic acid

[0180] 5-morpholino-3-(4,5,7-trifluorobenzothiazol-2-yl)methylindole-N-acetic acid was prepared in a manner analogous to that setforth in Example 2, except that 5-morpholinoindole was used instead of5-chloroindole. ¹H NMR (DMSO-d₆, 300 MHz) δ 7.64-7.72 (m, 1H), 7.34 (s,1H), 7.26 (d, J=9.0 Hz, 1H), 7.06 (d, J=2.4 Hz, 1H), 6.91 (dd, J₁=9.0Hz, J₂=2.4 Hz, 1H), 4.95 (s, 2H), 4.60 (s, 2H), 3.70-3.73 (m, 4H),2.97-3.00 (m, 4H); LRMS calcd for C₂₂H₁₈F₃N₃O₃S: 461.0; found 462(M+1)⁺. Anal. Calcd for C₂₂H₁₈F₃N₃O₃S·1H₂O: C, 55.11; H, 4.20; N, 8.76;S, 6.69. Found: C, 55.11; H, 4.05; N, 8.57; S, 6.50.

EXAMPLE 18 Preparation of6-morpholino-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-aceticacid Preparation of 4-Morpholino-2-nitrotoluene

[0181] A mixture of 4-fluoro-2-nitrotoluene (15.34 g, 98.9 mmol),morpholine (12.94 mL, 49.4 mmol) and K₂CO₃ (6.83 g, 148.3 mmol) werediluted in anhydrous DMSO (250 mL) at room temperature with stirring.The mixture was heated to 120° C. for 24 h. After cooling to roomtemperature, H₂O was added and the resultant mixture was extracted withEtOAc (3×, 75 mL). The organic layer was washed with sat'd brine (100mL), dried over MgSO₄, filtered and concentrated in vacuo. The remainingsolid was triturated in hepatane (200 mL) and filtered to give thedesired material (8.00 g, 36.4%) as a yellow powder: R_(f) 0.40 (25%ethyl acetate in heptane). ¹H NMR (DMSO-d₆, 300 MHz) δ 7.40 (d, J=2.7Hz, 1H), 7.30 (d, J=8.7 Hz, 1H), 7.20 (dd, J₁=8.7 Hz, J₂=2.7 Hz, 1H),3.70 (t, J=4.8 Hz, 4H), 3.35 (t, J=4.8 Hz, 4H), 2.36 (s, 3H).

Preparation of 6-Morpholinoindole

[0182] Under an atmosphere of nitrogen, a solution of4-morpholino-2-nitrotoluene (7.1 g, 31.9 mmol) in DMF (100 mL) wastreated with dimethylformamide dimethyl acetal (4.92 mL, 37.1 mmol) andpyrrolidine (2.67 mL, 31.9 mL). The mixture was heated to 100° C. andmaintained for 12 h. After cooling, the mixture was concentrated invacuo to give the desired intermediate as a brick-red solid. The crudeintermediate was dissolved in glacial HOAc (250 mL) and warmed to 85° C.Zn (18.17 g, 0.278 mol) was added to the solution portionwise over 30min. The mixture was heated for 4 h. After cooling to room temperature,the mixture was neutralized with sat'd NaHCO₃ and extracted with Et₂O(3×, 300 mL). The combined organics were washed with sat'd brine, driedover MgSO₄, filtered and concentrated in vacuo. The residue was purifiedby SiO₂ flash chromatography (heptane to 2:1 heptane/EtOAc) to give thedesired material as a white crystalline powder (1.0 g, 11% over 2steps): R_(f) 0.50 (2:1 Heptane/EtOAc); ¹H NMR (DMSO)-d₆, 300 MHz) δ10.73 (br s, 1H), 7.35 (d, J=8.4 Hz, 1H), 7.11 (d, J=2.4 Hz, 1H), 6.80(s, 1H), 6.73 (dd, J₁=8.4 Hz, J₂=2.4 Hz, 1H), 6.25 (d, J=2.4 Hz, 1H),3.72 (t, J=4.8 Hz, 4H), 3.02 (t, J=4.8 Hz, 1H).

Preparation of 6-morpholino-3-(4,5,7-trifluorobenzothiazol-2-yl)methylindole-N-acetic acid

[0183] 6-morpholino-3-(4,5,7-trifluorobenzothiazol-2-yl)methylindole-N-acetic acid was prepared in a manner analogous to that setforth in Example 2, except that 6-morpholinoindole was used instead of5-chloroindole in step 1: mp 178-180° C.; ¹H NMR (DMSO-d₆, 300 MHz) δ7.66-7.72 (m, 1H), 7.37 (d, J=8.4 Hz, 1H), 7.29 (s, 1H), 7.06 (d, J=2.4Hz, 1H), 6.84 (d, J=8.4 Hz, 1H), 4.96 (s, 2H), 4.58 (s, 2H), 3.37-3.75(m, 4H), 3.09-3.13 (m, 4H); LRMS calcd for C₂₂H₁₈F₃N₃O₃S: 461.0; found462 (M+1)⁺. Anal. Calcd for C₂₂H₁₈F₃N₃O₃S CH₂Cl₂ 0.50H₂O: C, 49.74; H,3.72; N, 7.57; S, 5.77 Found C, 49.73; H, 3.36; N, 7.69; S, 5.58

EXAMPLE 19 Preparation of5-phenoxy-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-aceticacid

[0184]

5-Phenoxy-2-nitrotoluene

[0185] A solution of phenol (12.16 g, 0.129 mol) in anhydrous DMSO wastreated with KCO₃ (17.88 g, 0.129 mol) and stirred at room temperaturefor 15 min. 5-Fluoro-2-nitrotoluene (13.38 g, 0.086 mol) was added tothe solution via syringe. The resultant mixture was heated to 80° C. for12 h. After cooling to room temperature, the mixture was poured into H₂O(100 mL). After extraction with EtOAc (2×, 100 mL), the organics werecombined and washed with a sat'd brine solution, drieds over MgSO₄,filtered and concentrated in vacuo. The residue was purified by flashcolumn chromatography (heptane to 8:1 heptane/EtOAc) to give the desiredmaterial as a yellow crystalline solid (12.50 g, 63%): R_(f) 0.60 (85%heptane/15% EtOAc); ¹H NMR (DMSO-d₆, 300 MHz) δ 8.05 (d, J=9.0 Hz, 1H),7.44-7.47 (m, 2H), 7.23-7.29 (m, 1H), 7.12-7.16 (m, 2H), 7.04 (d, J=2.7Hz, 1H), 6.90 (dd, J₁=9.0 Hz, J₂=2.7 Hz, 1H), 2.51 (s, 3H).

5-Phenoxyindole

[0186] A solution of 5-phenoxy-2-nitrotoluene (10.03 g, 0.0428 mol) inanhydrous DMF was treated with N,N-dimethylformamide dimethyl diacetal(6.73 mL, 0.0508 mol) and pyrrolidine (3.63 mL, 0.0438 mol) and heatedto 110 C for 2.5 h. After cooling to room temperature, the mixture wasdiluted with EtOAc (500 mL) and washed H₂ O (500 mL). The organics weredried over MgSO4, filtered and concentrated in vacuo. The crudeintermediate was dissolved in glacial HOAc (250 mL) and warmed to 85° C.Zn (24.62 g, 0.377 mol) was added to the solution portion wise over 30min. The mixture was heated for 4 h. After cooling to room temperature,the mixture was neutralized with sat'd NaHCO₃ and extracted with Et₂O(3×, 300 mL). The combined organics were washed with sat'd brine, driedover MgSO₄, filtered and concentrated in vacuo. The residue was purifiedby SiO₂ flash chromatography (heptane to 2:1 heptane/EtOAc) to give thedesired material as a white crystalline powder (3.1 g, 34% over 2steps): R_(f) 0.50 (2:1 Heptane/EtOAc); ¹H NMR (DMSO-d₆, 300 MHz) δ11.12 (br s, 1H), 7.48 (s, 1H), 7.30-7.38 (m, 1H), 7.25-7.29 (m, 2H),7.17 (d, J=2.7 Hz, 1H), 6.89-7.02 (m, 1H), 6.86-6.88 (m, 2H), 6.80 (dd,J₁=8.7 Hz, J₂=2.4 Hz, 1H), 6.37 (m, 1H).

Preparation of 5-phenoxy-3-(4,5,7-triflurobenzothiazol-2-yl)methylindole-N-acetic acid

[0187] 5-phenoxy-3-(4,5,7-trifluorobenzothiazol-2-yl)methylindole-N-acetic acid was prepared in a manner analogous to that setforth in Example 2, except that 5-phenoxyindole was used instead of5-chloroindole in step 1: mp 128-130° C.; R_(f) 0.45 (10% methanol inchloroform ); ¹H NMR (DMSO-d₆, 300 MHz) δ 7.65-7.70 (m, 1H), 7.47 (s,1H), 7.42 (d, J=8.4 Hz, 1H), 7.21-7.27 (m, 3H), 6.98 (m, 1H), 6.83-6.90(m, 3H), 5.02 (s, 2H), 4.60 (s, 2H); LRMS calcd for C₂₄H₁₅F₃N₂O₃S:468.0; found 467.0 (M−1)⁻. Anal. Calcd for C₂₄H₁₅F₃N₂O₃S: C, 55.11; H,4.20; N, 8.76; S, 6.69. Found: C, 55.11; H, 4.05; N, 8.57; S, 6.50.

EXAMPLE 20 Preparation of7-fluoro-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-acetic acid

[0188] 7-Fluoro-3-(4,5,7-trifluorobenzothiazol-2-yl)methylindole-N-acetic acid was prepared in a manner analogous to that setforth in Example 2, except that 7-fluoroindole was used instead of5-chloroindole in step 1: mp 194-196° C.; R_(f) 0.60 (10% methanol inchloroform); ¹H NMR (DMSO-d₆, 300 MHz) δ 7.67-7.73 (m, 1H), 7.46 (s,1H), 7.35 (d, J=7.2 Hz, 1H), 6.89-6.99 (m, 2H), 5.06 (s, 2H), 4.64 (s,2H); LRMS calcd for C₁₈H₁₀F₄N₂O₂S.H₂O: C,50.23; H, 3.28; N, 6.51; S,7.45. Found C, 50.70; H, 2.52; N, 6.60; S, 7.57. 394.0; found 395.0(M+1)⁺. Anal. Calcd for C₁₈H₁₀F₄N₂O₂S

EXAMPLE 21 Preparation of7-bromo-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-acetic acid

[0189] 7-bromo-3-(4,5,7-trifluorobenzothiazol-2-yl)methylindole-N-acetic acid was prepared in a manner analogous to that setforth in Example 2, except that 7-bromoindole was used instead of5-chloroindole in step 1: mp 228-230° C.; R_(f) 0.40 (10% methanol inchloroform); ¹H NMR (DMSO-d₆, 300 MHz) δ 7.65-7.74 (m, 1H), 7.57 (d,J=7.8 Hz, 1H), 7.49 (s, 1H), 7.32 (d, J=7.8 Hz, 1H), 6.94 (t, J=7.8 Hz,1H), 5.29 (s, 2H), 4.65 (s, 2H); LRMS calcd for C₁₈H₁₀F₃N₂O₂SBr: 454.0for (⁷⁹Br and 456.0 for ⁸¹Br); found 453.0 (M−1)⁻ and 455.0 (M−1)⁻. AnalCalcd for C₁₈H₁₀F₃N₂O₂SBr: C, 47.49; H, 2.21; N, 6.15; S, 7.04. Found:C, 47.65;H, 2.27; N, 6.15; S, 6.98.

EXAMPLE 22 Preparation of7-chloro-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-acetic acid

[0190] 7-chloro-3-(4,5,7-trifluorobenzothiazol-2-yl)methylindole-N-acetic acid was prepared in a manner analogous to that setforth in Example 2, except that 7-chloroindole was used instead of5-chloroindole in step 1: mp 228-230° C.; R_(f) 0.38 (10% methanol inchloroform ); ¹H NMR (DMSO-d₆, 300 MHz) δ 7.62-7.73 (m, 1H), 7.52 (d,J=7.5 Hz, 1H), 7.49 (s, 1H), 7.15 (d, J=7.5 Hz, 1H), 7.00 (t, J=7.5 Hz,1H), 5.25 (s, 2H), 4.65 (s, 2H); LRMS calcd for C₁₈H₁₀F₃N₂O₂SCl: 410.0;found 409.0 (M−1)⁻. Anal. Calcd for C₁₈H₁₀F₃N₂O₂SCl: C, 52.63; H, 2.45;N, 6.82; S, 7.81. Found: C, 52.60; H, 2.54; N, 6.66; S, 7.59.

EXAMPLE 23 3-[5-Fluorbenzothiazole-2-yl]methyl-indole-N-acetic Acid

[0191]

[0192] 3-[5-fluorbenzothiazole-2-yl]methyl-indole-N-acetic acid wasprepared in a manner analogous to that set forth in Example 3, except2-amino-4-fluorothiophenol hydrochloride was used instead of2-amino-4,5,7-trifluorothiophenol hydrochloride in step 6: mp 208° C.(decomp); R_(f)0.10 (10% methanol in diehloromethane) ¹H NMR (DMSO-d₆,300 MHz) δ 12.91 (s, 1 H), 7.98 (dd, J=8.9, 5.6 Hz: 1 H), 7.78 (dd,J=10.0, 2.6 Hz, 1 H), 7.50 (d, J=7.8 Hz, 1 H), 7.40 (s, 1 H), 7.37 (d,J=7.8 Hz, 1 H), 7.26 (dt, J=8.9, 2.4 Hz, 1 H), 7.13 (t, J=7.8 Hz, 1 H),7.01 (t, J=7.8 Hz, 1 H), 5.01 (s, 2 H), 4.56 (s, 2 H); LRMS m/z 341.0(M+1)⁺, 339.0 (M−1). Anal. Calcd for C₁₈H₁₃FN₂O₂S: C, 63.52; H, 3.85; N,8.23; S, 9.42; Found: C, 63.40; H, 3.80; N, 8.37; S, 9.43.

EXAMPLE 24 3-[6-Fluorbenzothiazole-2-yl]methyl-indole-N-acetic Acid

[0193] 3-[6-fluorbenzothiazole-2-yl]methyl-indole-N-acetic acid wasprepared in a manner analogous to that set forth in Example 3, except2-amino-5-fluorothiophenol hydrochloride was used instead of2-amino-4,5,7-trifluorothiophenol hydrochloride in step 6: mp 203° C.(decomp) R_(f)0.13 (10% methanol in diehloromethane); ¹H NMR (DMSO-d₆,300 MHz) δ 12.91 (s, 1 H), 7.95 (dd, J=8.9, 5.0 Hz: 1 H), 7.86 (dd,J=8.8, 2.8 Hz, 1 H), 7.50 (d, J=7.5 Hz, 1 H), 7.40-7.35 (m, 2 H), 7.32(dt, J=8.9, 2.7 Hz, 1 H), 7.13 (t, J=7.6 Hz, 1 H), 7.00 (t, J=7.6 Hz, 1H), 5.01 (s, 2 H), 4.54 (s, 2 H); LRMS m/z 341.0 (M+1)⁺, 339.0 (M−1.Anal. Calcd for C₁₈H₁₃FN₂O₂S: C, 63.52; H, 3.85; N, 8.23; S, 9.42.Found: C, 63.52; H, 3.86; N, 8.35; S, 9.53.

[0194] The compounds of Examples 25-32 were prepared essentiallyaccording to the procedures set forth above in examples 1 and/or 2 withappropriate substitution of starting materials.

EXAMPLE 253-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-2-propionic acid

[0195]

[0196] mp 176-177° C.; R_(f) 0.34 (20% methanol in dichlormethane); ¹HNMR (DMSO-d₆, 300 MHz) δ 7.60-7.73 (m, 1H), 7.60 (s, 1H), 7.52 (d, J=8.1Hz, 1H), 7.44 (d, J=8.1 Hz, 1H), t, J=7.5 Hz, 1H), 7.02 (t, J=7.5 Hz,1H), 5.35 (q, J=8.1 Hz, 1H), 4.64 (s, 2H), 1.72 (d, J=8.1 Hz, 3H) ; LRMScalcd for C₁₉H₁₃F₃N₂O₂S: 390.0; Found 391.0 (M+1)⁺. Anal. Calcd forC₁₉H₁₃F₃N₂O₂SH₂O: C, 55.88; H, 3.70; N, 6.86; S, 7.85 Found: C, 56.09;H, 3.31; N, 6.89; S, 7.99.

EXAMPLE 263-(4-5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-3-propionic acid

[0197]

[0198] mp 200-201° C.; R_(f) 0.50 (20% methanol in dichloromethane); ¹HNMR (DMSO-d₆, 300 MHz) δ 7.63-7.71 (m, 1H), 7.51 (s, 1H), 7.47 (d, J=3.0Hz, 2H), 7.14 (t, J=7.5 Hz, 1H), 7.00 (t, J=7.5 Hz, 1H), 4.61 (s, 2H),4.39 (t, J=6.6 Hz, 2H), 2.75 (t, J=6.6 Hz, 2H); LRMS calcd forC₁₉H₁₃F₃N₂O₂S: 390.0; Found 391.0 (M+1)⁺. Anal Calcd for C₁₉H₁₃F₃N₂O₂S:C, 58.46; H, 3.36; N, 7.18; S, 8.21 Found: C, 58.63; H, 3.40; N, 7.20;S, 8.30.

EXAMPLE 27 Preparation of6-Bromo-3-(5-trifluoromethylbenzothiazol-2-yl)methyl-indole-N-aceticacid

[0199] mp 265-267° C.; R_(f) 0.19 (20% methanol in dichloromethane); ¹HNMR (DMSO-d₆, 300 MHz) δ 8.28 (s, 1H), 8.22 (d, J=8.7 Hz, 1H), 7.67-7.69(m, 2H), 7.43-7.47 (m, 2H), 7.14 (d, J=9.0 Hz, 1H), 5.04. (s, 2H), 4.61(s, 2H); LRMS calcd for C₁₉H₁₂F₃N₂O₂SBr:469.0; Found 469.0 (M+1)⁺ forBr=79. Anal. Calcd for C₁₉H₁₂F₃N₂O₂SBr: C, 48.63; H, 2.58; N, 5.97; S,6.83. Found: C, 48.60; H, 2.63; N, 5.88; S, 6.91.

EXAMPLE 286-Methoxy-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-aceticacid

[0200] mp 118-120° C.; R_(f) 0.27 (20% methanol in dichloromethane); ¹HNMR (DMSO-d₆, 300 MHz) δ 7.63-7.73 (m, 1H), 7.39 (s, 1H), 7.28 (d, J=8.7Hz, 1H), 7.07 (s, 1H), 6.78 (d, J=8.7 Hz, 1H), 4.97 (s, 2H), 4.61 (s,2H); 3.07 (s, 3H); LRMS calcd for C₁₉H₁₃F₃N₂O₃S: 406.0; Found 407.0(M+)⁺. Anal. Calcd for C₁₉H₁₃F₃N₂O₃SH₂O: C, 53.77; H, 3.56; N, 6.60; S,7.56 Found: C, 53.87; H, 3.56; N. 6.67; S, 7.67.

EXAMPLE 294-Chloro-3-(4,5,7-trifluorobenzothiazol-2yl)methyl-indole-N-acetic acid

[0201]

[0202] mp 203-206° C.; R_(f) 0.24 (20% methanol in dichloromethane); ¹HNMR (DMSO-d₆, 300 MHz) δ 7.63-7.71 (m, 1H), 7.57 (s, 1H), 7.33 (d, J=9.0Hz, 1H), 7.12 (dd, J (₁)=9.0, J (₂)=7.8 Hz, 1H), 7.03 (d, J=7.8 Hz, 1H),5.08 (s, 2H), 4.78 (s, 2H); LRMS calcd for C₁₈H₁₀F₃N₂O₂SCl: 410.0; Found411.0 (M+1)⁺ and 409.0 (M−1)⁻.

EXAMPLE 305-Methoxy-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-aceticacid

[0203]

[0204] mp 165-167° C.; R_(f) 0.37 (20% methanol in dichloromethane); ¹HNMR (DMSO-d₆, 300 MHz) δ 7.61-7.70 (m, 1H), 7.35 (d, J=9.0 Hz, 1H), 7.26(s, 1H), 6.90 (s, 1H), 6.64 (d, J=9.0 Hz, 1H), 4.79 (s, 2H); 4.56 (s,2H), 3.72 (s, 3H); LRMS calcd for C₁₀H₁₃F₃N₂O₂S: 406.0; Found 407.0(M+1)⁺ and 405.0 (M−1)⁺.

EXAMPLE 315-Bromo-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-acetic acid

[0205] mp 209-294° C.; R_(f) 0.18 (20% methanol in dichloromethane); ¹HNMR (DMSO-d₆, 300 MHz) δ 7.78 (d, J=1.8 Hz, 1H), 7.65-7.73 (m, 1H), 7.49(s, 1H), 7.61 (d, J=9.0 Hz, 1H), 7.25 (dd, J (₁)=9.0 Hz, J (₂)=1.8 Hz,1H), 5.04 (s, 2H); 4.64 (s, 2H); LRMS calcd for C₁₈H₁₀F₃N₂O₂SBr: 455.0;Found 455.0 (M+1)⁺ for Br 79 and 457 (M+1)⁺ for Br 81.

EXAMPLE 32 3-(6-chlorobenzothiazol-2-yl)methyl-indole-N-acetic acid

[0206]

[0207] Representative compounds of the invention were tested for theirpotency, selectivity and efficacy as inhibitors of human aldosereductase. The potency or aldose reductase inhibiting effects of thecompounds were tested using methods similar to those described by Buteraet al. in J. Med. Chem. 1989, 32, 757. Using this assay, theconcentrations required to inhibit human aldose reductase (hALR2)activity by 50% (IC50) were determined.

[0208] In a second assay, a number of the same compounds were tested fortheir ability to inhibit aldehyde reductase (hALR1), a structurallyrelated enzyme. The test, method employed were essentially thosedescribed by Ishii, et al., J. Med. Chem. 1996 39: 1924. Using thisassay, the concentrations required to inhibit human aldehyde reductaseactivity by 50% (IC50) were determined.

[0209] From these data, the hALR1/hALR2 ratios were determined. Sincehigh potency of test compounds as inhibitors of aldose reductase isdesirable, low hALR2 IC50 values are sought. On the other hand, highpotency of test compounds as inhibitors of aldehyde reductase isundesirable, and high hALR1 IC50s values are sought. Accordingly, thehALR1/hALR2 ratio is used to determine the selectivity of the testcompounds. The importance of this selectivity is described in Kotani, etal., J. Med. Chem. 40: 684, 1997.

[0210] The results of all these tests are combined and illustrated inTable 1. Example hALR2 HALR1 HALR1/ # (IC50) (IC50) hALR2 1 8 nM 13,000nM 1,200 2 10 nM 11,000 nM 1,100 3 5 nM 27,000 nM 5,400 4 8 nM 34,000 nM4,250 5 6 nM 21,000 nM 3,500 6 8 nM 2,700 nM 340 7 12 nM 4,800 nM 400 87 nM 7,500 nM 1,100 9 11 nM 21,000 nM 1,900 10 5 nM 13,000 nM 2,600 1199 nM 5,600 nM 57 12 103 nM 10,000 nM 98 13 73 nM 13,000 nM 178 14 101nM 16,000 160 15 53 nM 10,000 190 16 25 nM 6,200 nM 248 17 8 nM 41,000nM 5,100 18 15 nM >100 nM >6,700 19 30 nM 11,000 nM 370 20 7 nM 7,000 nM1,000 21 14 nM 18,000 nM 1,300 22 9.1 nM 19,000 nM 2,100 23 9 nM 6,500720 24 1,040 nM 4,500 nM 4 25 160 nM 6,500 nM 41 26 17 nM 88,000 nM5,200 27 52 nM <5,000 nM <96 28 5 nM 12,000 nM 2,400 29 11 nM 14,0001,270 30 7.7 nM 21,000 nM 2,700 31 13 nM 9,700 746 32 660 nM Not TestedNot Tested Tolrest 13 nM 1,940 nM 149 at

[0211] The results show the superior potency, selectivity and efficacyof representative compounds of the invention. Such compounds are usefulin the treatment of chronic complications arising from diabetesmellitus, such as diabetic cataracts, retinopathy and neuropathy.Accordingly, an aspect of the invention is treatment of suchcomplications with the inventive compounds; treatment includes bothprevention and alleviation. The compounds are useful in the treatmentof, for example, diabetic cataracts, retinopathy, nephropathy andneuropathy.

[0212] In a third, optional, set of experiments, the compounds can beassayed for their ability to normalize or reduce sorbitol accumulationin the sciatic nerve of streptozotocin-induced diabetic rats. The testmethods employed to determine the efficacy are essentially those ofMylari, et al., J. Med. Chem. 34: 108, 1991.

[0213] The invention and the manner and process of making and using it,are now described in such full, clear, concise and exact terms as toenable any person skilled in the art to which it pertains, to make anduse the same. It is to be understood that the foregoing describespreferred embodiments of the present invention and that modificationsmay be made therein without departing from the spirit or scope of thepresent invention as set forth in the claims. To particularly point outand distinctly claim the subject matter regarded as invention, thefollowing claims conclude this specification.

We claim:
 1. A compound of the formula:

wherein A is a C₁-C₄ alkylene group optionally substituted with C₁-C₂alkyl or mono- or disubstituted with halogen; Z is a bond, O, S, C(O)NH,or C₁-C₃ alkylene optionally substituted with C₁-C₂ alkyl; R₁ ishydrogen, alkyl having 1-6 carbon atoms, halogen, 2-, 3-, or 4-pyridyl,or phenyl, where the phenyl or pyridyl is optionally substituted with upto three groups selected from halogen, hydroxy, C₁-C₆ alkoxy, C₁-C₆alkyl, nitro, amino, or mono- or di(C₁-C₆)alkylamino; R₂, R₃, R₄ and R₅are each independently hydrogen, halogen, nitro, or an alkyl group of1-6 carbon atoms (which may be substituted with one or more halogens);OR₇, SR₇, S(O)R₇, S(O)₂N(R₇)₂, C(O)N(R₇)₂, or N(R₇)₂, wherein each R₇ isindependently hydrogen, an alkyl group of 1-6 carbon atoms (which may besubstituted with one or more halogens) or benzyl, where the phenylportion is optionally substituted with up to three groups independentlyselected from halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, amino, and mono- ordi(C₁-C₆)alkylamino; phenyl or heteroaryl such as 2-, 3- or 4-imidazolylor 2-, 3-, or 4-pyridyl, each of which phenyl or heteroaryl isoptionally substituted with up to three groups independently selectedfrom halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, amino, and mono- ordi(C₁-C₆)alkylamino; phenoxy where the phenyl portion is optionallysubstituted with up to three groups independently selected from halogen,C₁-C₆ alkyl, C₁-C₆ alkoxy, amino, and mono- or di(C₁-C₆) alkylamino; ora group of the formula

where J is a bond, CH₂, oxygen, or nitrogen; and each r is independently2 or 3; R₆ is hydroxy or a prodrug group; R_(a) is hydrogen, C₁-C₆alkyl, fluoro, or trifluoromethyl; and Ar represents a phenyl groupoptionally substituted with up to 5 groups independently selected fromhalogen, an alkyl group of 1-6 carbon atoms (which may be substitutedwith one or more halogens), nitro, OR₇, SR₇, S(O)R₇, S(O)₂R₇ or N(R₇)₂wherein R₇ is hydrogen, an alkyl group of 1-6 carbon atoms (which may besubstituted with one or more halogens) or benzyl, where the phenylportion is optionally substituted with up to three groups independentlyselected from halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, amino, and mono- ordi(C₁-C₆)alkylamino, or the phenyl group may be condensed with benzowhere the benzo is optionally substituted with one or two of halogen,cyano, nitro, trifluoromethyl, perfluoroethyl, trifluoroacetyl, or(C₁-C₆)alkanoyl, hydroxy, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio,trifluoromethoxy, trifluoromethylthio, (C₁-C₆)alkylsulfinyl, (C₁-C₆)alkylsulfonyl; a heterocyclic 5-membered ring having one nitrogen,oxygen or sulfur, two nitrogens one of which may be replaced by oxygenor sulfur, or three nitrogens one of which may be replaced by oxygen orsulfur, said heterocyclic 5-membered ring substituted by one or twofluoro, chloro, (C₁-C₆)alkyl or phenyl, or condensed with benzo, orsubstituted by one of pyridyl, furyl or thienyl, said phenyl or benzooptionally substituted by one of iodo, cyano, nitro, perfluoroethyl,trifluoroacetyl, or (C₁-C₆)alkanoyl, one or two of fluoro, chloro,bromo, hydroxy, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio,trifluoromethoxy, trifluoromethylthio, (C₁-C₆)alkylsulfinyl,(C₁-C₆)alkylsulfonyl or trifluoromethyl, or two fluoro or twotrifluoromethyl with one hydroxy or one (C₁-C₆)alkoxy, or one or,preferably, two fluoro and one trifluoromethyl, or three fluoro, saidpyridyl, furyl or thienyl optionally substituted in the 3-position byfluoro, chloro, bromo, (C₁-C₆)alkyl or (C₁-C₆)alkoxy; a heterocyclic6-membered ring having one to three nitrogen atoms, or one or twonitrogen atoms and one oxygen or sulfur, said heterocyclic 6-memberedring substituted by one or two (C₁-C₆)alkyl or phenyl, or condensed withbenzo, or substituted by one of pyridyl, furyl or thienyl, said phenylor benzo optionally substituted by one of iodo or trifluoromethylthio,or one or two of fluoro, chloro, bromo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₁-C₆)alkylthio, (C₁-C₆)alkylsulfinyl, (C₁-C₆)alkylsulfonyl, ortrifluoromethyl, and said pyridyl, furyl or thienyl optionallysubstituted in the 3-position by fluoro, chloro, (C₁-C₆)alkyl or(C₁-C₆)alkoxy; said benzo-condensed heterocyclic 5-membered or6-membered rings optionally substituted in the heterocyclic 5-memberedor 6-membered ring by one of fluoro, chloro, bromo, methoxy, ortrifluoromethyl; oxazole or thiazole condensed with a 6-memberedaromatic group containing one or two nitrogen atoms, with thiophene orwith furane, each optionally substituted by one of fluoro, chloro,bromo, trifluoromethyl, methylthio or methylsulfinyl; imidazolopyridineor triazolopyridine optionally substituted by one of trifluoromethyl,trifluoromethylthio, bromo, or (C₁-C₆)alkoxy, or two of fluoro orchloro; thienothiophene or thienofuran optionally substituted by one offluoro, chloro or trifluoromethyl; thienotriazole optionally substitutedby one of chloro or trifluoromethyl; naphthothiazole; naphthoxazole; orthienoisothiazole.
 2. A compound according to claim 1, wherein Ar isaryl or heteroaryl, each of which is substituted with up to four groupsindependently selected from hydrogen, fluorine, chlorine, bromine,trifluoromethyl and nitro.
 3. A compound according to claim 1, whereinAr is a substituted phenyl of Formula II or a substituted benzothiazoleof Formula III

wherein R₈, R₈′, R₉, R₉′, R₁₀, R₁₁, R₁₂, R₁₃ and R₁₄ are independentlyhydrogen, fluorine, chlorine, bromine, trifluoromethyl or nitro.
 4. Acompound according to claim 3, wherein A is methylene and Z is a bond.5. A compound according to claim 3, wherein R_(a) is hydrogen and Z is abond.
 6. A compound according to claim 3, wherein A is methylene, R_(a)is hydrogen, and Z is a bond.
 7. A compound according to claim 6,wherein Ar is a substituted benzothiazole of Formula III.
 8. A compoundaccording to claim 7, wherein at least one of R₁₁, R₁₂, R₁₃, and R₁₄ istrifluoromethyl.
 9. A compound according to claim 8, wherein R₁₂ istrifluoromethyl.
 10. A compound according to claim 7, wherein R₁₁, R₁₂,and R₁₄ are fluorines and R₁₃ is hydrogen.
 11. A compound according toclaim 10, wherein R₆ is hydrogen.
 12. A compound according to claim 10,wherein R₆ is C₁-C₆ alkyl.
 13. A compound according to claim 6, whereinAr is a substituted phenyl of Formula II.
 14. A compound according toclaim 13, wherein at least one of R₈, R_(8′), R₉, R_(9′), R₁₀ istrifluoromethyl.
 15. A compound according to claim 14, wherein R₉ istrifluoromethyl.
 16. A compound according to claim 15, wherein R₈,R_(8′), R₉, R_(9′), R₁₀ are fluorines and R₁₃ is hydrogen.
 17. Acompound according to claim 16, wherein R₆ is hydrogen.
 18. A compoundaccording to claim 16, wherein R₆ is C₁-C₆ alkyl.
 19. A compoundaccording to claim 1, which is3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-acetic acid, ethylEster.
 20. A compound according to claim 1, which is3-(4,5,7-trifluorobenzothiazol-2yl)methyl-indole-N-acetic acid.
 21. Acompound according to claim 1, which is5-chloro-3-(4,5,7-Trifluorobenzothiazol-2-yl)methyl-indole-N-aceticacid.
 22. A compound according to claim 1, which is5-chloro-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-aceticacid.
 23. A compound according to claim 1, which is 2-methyl-3-(4,5,7trifluorobenzothiazol-2-yl)methyl-indole-N-acetic acid.
 24. A compoundaccording to claim 1, which is5-methyl-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-aceticacid.
 25. A compound according to claim 1, which is7-methyl-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-aceticacid.
 26. A compound according to claim 1, which is6-chloro-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-aceticacid.
 27. A compound according to claim 1, which is5-benzyloxy-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-aceticacid.
 28. A compound according to claim 1, which is6-fluoro-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-aceticacid.
 29. A compound according to claim 1, which is5-fluoro-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-aceticacid.
 30. A compound according to claim 1, which is6-methyl-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-aceticacid.
 31. A compound according to claim 1, which is3-(5-trifluoromethylbenzothiazol-2-yl)methyl-indole-N-acetic acid.
 32. Acompound according to claim 1, which is5-Methyl-3-(5-Trifluoromethylbenzothiazol-2-yl)methyl-indole-N-aceticacid.
 33. A compound according to claim 1, which is3-(3-nitrophenyl)methyl-indole-N-acetic acid.
 34. A compound accordingto claim 1, which is 3-(3-nitrophenyl)methyl-indole-N-acetic acid, ethylester.
 35. A compound according to claim 1, which is3-(3-nitrophenyl)methyl-indole-N-acetic acid.
 36. A compound accordingto claim 1, which is2-phenyl-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-aceticacid.
 37. A compound according to claim 1, which is5-phenyl-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-aceticacid.
 38. A compound according to claim 1, which is6-phenyl-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-aceticacid.
 39. A compound according to claim 1, which is5-morpholino-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-aceticacid.
 40. A compound according to claim 1, which is6-morpholino-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-aceticacid.
 41. A compound according to claim 1, which is5-phenoxy-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-aceticacid.
 42. A compound according to claim 1, which is7-fluoro-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-aceticacid.
 43. A compound according to claim 1, which is7-bromo-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-acetic acid.44. A compound according to claim 1, which is-chloro-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-acetic acid.45. A compound according to claim 1, which is3-[[5-Fluorbenzothiazole-2-yl]methyl]-indole-N-acetic acid.
 46. Acompound according to claim 1, which is3-[[6-Fluorbenzothiazole-2-yl]methyl]-indole-N-acetic acid.
 47. Apharmaceutical composition comprising an effective amount of a compoundaccording to any one of claims
 1. 48. A method of preventing oralleviating chronic complications arising from diabetes mellitus, whichcomprises administering to a mammal in need of such treatment aneffective amount of a compound according to claim
 1. 49. A methodaccording to claim 37 wherein the complications are selected from thegroup consisting of diabetic cataracts, retinopathy, nephropathy andneuropathy.
 50. A compound according to claim 3, wherein Ar is asubstituted benzothiazole of Formula III, R₁₂ is trifluoromethyl, A ismethylene, methylene substituted with a methyl group, or ethylene, andR₂, R₃, R₄ and R₅, in combination, represent one of bromo, cyano ornitro, one or two of fluoro, chloro, hydroxy, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, or trifluoromethyl, or two fluoro or two methyl with onehydroxy or one (C₁-C₆)alkoxy, or one or, preferably, two fluoro and onemethyl, or three fluoro groups.